For best viewing of the website please use Mozilla Firefox or Google Chrome.
Volume 34 Issue 2
April 2019
Article Contents
Citation: Qiang Zhang, Nishi R. Sharma, Zhi-Ming Zheng, Mingzhou Chen. Viral Regulation of RNA Granules in Infected Cells [J].VIROLOGICA SINICA, 2019, 34(2) : 175-191.

Viral Regulation of RNA Granules in Infected Cells

  • RNA granules are cytoplasmic, microscopically visible, non-membrane ribo-nucleoprotein structures and are important posttranscriptional regulators in gene expression by controlling RNA translation and stability. TIA/G3BP/PABP-specific stress granules (SG) and GW182/DCP-specific RNA processing bodies (PB) are two major distinguishable RNA granules in somatic cells and contain various ribosomal subunits, translation factors, scaffold proteins, RNA-binding proteins, RNA decay enzymes and helicases to exclude mRNAs from the cellular active translational pool. Although SG formation is inducible due to cellular stress, PB exist physiologically in every cell. Both RNA granules are important components of the host antiviral defense. Virus infection imposes stress on host cells and thus induces SG formation. However, both RNA and DNA viruses must confront the hostile environment of host innate immunity and apply various strategies to block the formation of SG and PB for their effective infection and multiplication. This review summarizes the current research development in the field and the mechanisms of how individual viruses suppress the formation of host SG and PB for virus production.
  • 加载中
    1. Abrahamyan LG, Chatel-Chaix L, Ajamian L, Milev MP, Monette A, Clement JF, Song R, Lehmann M, DesGroseillers L, Laughrea M, Boccaccio G, Mouland AJ (2010) Novel Staufen1 ribonucleoproteins prevent formation of stress granules but favour encapsidation of HIV-1 genomic RNA. J Cell Sci 123:369-383
        doi: 10.1242/jcs.055897

    2. Anderson P, Kedersha N (2008) Stress granules: the Tao of RNA triage. Trends Biochem Sci 33:141-150
        doi: 10.1016/j.tibs.2007.12.003

    3. Anderson P, Kedersha N (2009) RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat Rev Mol Cell Biol 10:430-436
        doi: 10.1038/nrm2694

    4. Anderson P, Kedersha N, Ivanov P (2015) Stress granules, P-bodies and cancer. Biochim Biophys Acta 1849:861-870
        doi: 10.1016/j.bbagrm.2014.11.009

    5. Andrei MA, Ingelfinger D, Heintzmann R, Achsel T, Rivera-Pomar R, Luhrmann R (2005) A role for eIF4E and eIF4E-transporter in targeting mRNPs to mammalian processing bodies. RNA 11:717-727
        doi: 10.1261/rna.2340405

    6. Aqil M, Naqvi AR, Bano AS, Jameel S (2013) The HIV-1 Nef protein binds argonaute-2 and functions as a viral suppressor of RNA interference. PLoS ONE 8:e74472
        doi: 10.1371/journal.pone.0074472

    7. Ariumi Y, Kuroki M, Kushima Y, Osugi K, Hijikata M, Maki M, Ikeda M, Kato N (2011) Hepatitis C virus hijacks P-body and stress granule components around lipid droplets. J Virol 85:6882-6892
        doi: 10.1128/JVI.02418-10

    8. Bashkirov VI, Scherthan H, Solinger JA, Buerstedde JM, Heyer WD (1997) A mouse cytoplasmic exoribonuclease (mXRN1p) with preference for G4 tetraplex substrates. J Cell Biol 136:761-773
        doi: 10.1083/jcb.136.4.761

    9. Beckham CJ, Light HR, Nissan TA, Ahlquist P, Parker R, Noueiry A (2007) Interactions between brome mosaic virus RNAs and cytoplasmic processing bodies. J Virol 81:9759-9768
        doi: 10.1128/JVI.00844-07

    10. Berlanga JJ, Ventoso I, Harding HP, Deng J, Ron D, Sonenberg N, Carrasco L, de Haro C (2006) Antiviral effect of the mammalian translation initiation factor 2alpha kinase GCN2 against RNA viruses. EMBO J 25:1730-1740
        doi: 10.1038/sj.emboj.7601073

    11. Bhowmick R, Mukherjee A, Patra U, Chawla-Sarkar M (2015) Rotavirus disrupts cytoplasmic P bodies during infection. Virus Res 210:344-354
        doi: 10.1016/j.virusres.2015.09.001

    12. Bordeleau ME, Cencic R, Lindqvist L, Oberer M, Northcote P, Wagner G, Pelletier J (2006) RNA-mediated sequestration of the RNA helicase eIF4A by Pateamine A inhibits translation initiation. Chem Biol 13:1287-1295
        doi: 10.1016/j.chembiol.2006.10.005

    13. Borghese F, Michiels T (2011) The leader protein of cardioviruses inhibits stress granule assembly. J Virol 85:9614-9622
        doi: 10.1128/JVI.00480-11

    14. Buchan JR, Parker R (2009) Eukaryotic stress granules: the ins and outs of translation. Mol Cell 36:932-941
        doi: 10.1016/j.molcel.2009.11.020

    15. Burdick R, Smith JL, Chaipan C, Friew Y, Chen J, Venkatachari NJ, Delviks-Frankenberry KA, Hu WS, Pathak VK (2010) P body-associated protein Mov10 inhibits HIV-1 replication at multiple stages. J Virol 84:10241-10253
        doi: 10.1128/JVI.00585-10

    16. Burgess HM, Richardson WA, Anderson RC, Salaun C, Graham SV, Gray NK (2011) Nuclear relocalisation of cytoplasmic poly(A)-binding proteins PABP1 and PABP4 in response to UV irradiation reveals mRNA-dependent export of metazoan PABPs. J Cell Sci 124:3344-3355
        doi: 10.1242/jcs.087692

    17. Cassady KA, Gross M (2002) The herpes simplex virus type 1 U(S)11 protein interacts with protein kinase R in infected cells and requires a 30-amino-acid sequence adjacent to a kinase substrate domain. J Virol 76:2029-2035
        doi: 10.1128/jvi.76.5.2029-2035.2002

    18. Chahar HS, Chen S, Manjunath N (2013) P-body components LSM1, GW182, DDX3, DDX6 and XRN1 are recruited to WNV replication sites and positively regulate viral replication. Virology 436:1-7
        doi: 10.1016/j.virol.2012.09.041

    19. Chan SW, Egan PA (2005) Hepatitis C virus envelope proteins regulate CHOP via induction of the unfolded protein response. FASEB J 19:1510-1512
        doi: 10.1096/fj.04-3455fje

    20. Checkley MA, Nagashima K, Lockett SJ, Nyswaner KM, Garfinkel DJ (2010) P-body components are required for Ty1 retrotransposition during assembly of retrotransposition-competent virus-like particles. Mol Cell Biol 30:382-398
        doi: 10.1128/MCB.00251-09

    21. Chen D, Wilkinson CR, Watt S, Penkett CJ, Toone WM, Jones N, Bahler J (2008) Multiple pathways differentially regulate global oxidative stress responses in fission yeast. Mol Biol Cell 19:308-317
        doi: 10.1091/mbc.e07-08-0735

    22. Chen C, Ma X, Hu Q, Li X, Huang F, Zhang J, Pan T, Xia J, Liu C (2017) Moloney leukemia virus 10 (MOV10) inhibits the degradation of APOBEC3G through interference with the Vif-mediated ubiquitin-proteasome pathway. Retrovirology 14:56
        doi: 10.1186/s12977-017-0382-1

    23. Clavarino G, Claudio N, Dalet A, Terawaki S, Couderc T, Chasson L, Ceppi M, Schmidt EK, Wenger T, Lecuit M, Gatti E, Pierre P (2012) Protein phosphatase 1 subunit Ppp1r15a/GADD34 regulates cytokine production in polyinosinic:polycytidylic acid-stimulated dendritic cells. Proc Natl Acad Sci U S A 109:3006-3011
        doi: 10.1073/pnas.1104491109

    24. Corcoran JA, Johnston BP, McCormick C (2015) Viral activation of MK2-hsp27-p115RhoGEF-RhoA signaling axis causes cytoskeletal rearrangements, p-body disruption and ARE-mRNA stabilization. PLoS Pathog 11:e1004597
        doi: 10.1371/journal.ppat.1004597

    25. Cuevas RA, Ghosh A, Wallerath C (2016) MOV10 provides antiviral activity against RNA viruses by enhancing RIG-I-MAVS-independent IFN induction. J Immunol 196:3877-3886
        doi: 10.4049/jimmunol.1501359

    26. Dang Y, Kedersha N, Low WK, Romo D, Gorospe M, Kaufman R, Anderson P, Liu JO (2006) Eukaryotic initiation factor 2alpha-independent pathway of stress granule induction by the natural product pateamine A. J Biol Chem 281:32870-32878
        doi: 10.1074/jbc.M606149200

    27. Dauber B, Poon D, Dos Santos T, Duguay BA, Mehta N, Saffran HA, Smiley JR (2016) The herpes simplex virus virion host shutoff protein enhances translation of viral true late mrnas independently of suppressing protein kinase R and stress granule formation. J Virol 90:6049-6057
        doi: 10.1128/JVI.03180-15

    28. Decker CJ, Parker R (2012) P-bodies and stress granules: possible roles in the control of translation and mRNA degradation. Cold Spring Harb Perspect Biol 4:a012286

    29. Deng J, Harding HP, Raught B, Gingras AC, Berlanga JJ, Scheuner D, Kaufman RJ, Ron D, Sonenberg N (2002) Activation of GCN2 in UV-irradiated cells inhibits translation. Curr Biol 12:1279-1286
        doi: 10.1016/S0960-9822(02)01037-0

    30. Dhillon P, Rao CD (2018) Rotavirus induces formation of remodeled stress granules and P bodies and their sequestration in viroplasms to promote progeny virus production. J Virol 92:e01363-18

    31. Dinh PX, Beura LK, Das PB, Panda D, Das A, Pattnaik AK (2013) Induction of stress granule-like structures in vesicular stomatitis virus-infected cells. J Virol 87:372-383
        doi: 10.1128/JVI.02305-12

    32. Dougherty JD, White JP, Lloyd RE (2011) Poliovirus-mediated disruption of cytoplasmic processing bodies. J Virol 85:64-75
        doi: 10.1128/JVI.01657-10

    33. Durand S, Cougot N, Mahuteau-Betzer F, Nguyen CH, Grierson DS, Bertrand E, Tazi J, Lejeune F (2007) Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies. J Cell Biol 178:1145-1160
        doi: 10.1083/jcb.200611086

    34. Elkayam E, Faehnle CR, Morales M, Sun J, Li H, Joshua-Tor L (2017) Multivalent recruitment of human argonaute by GW182. Mol Cell 67:646-658.e643
        doi: 10.1016/j.molcel.2017.07.007

    35. Emara MM, Brinton MA (2007) Interaction of TIA-1/TIAR with West Nile and dengue virus products in infected cells interferes with stress granule formation and processing body assembly. Proc Natl Acad Sci U S A 104:9041-9046
        doi: 10.1073/pnas.0703348104

    36. Eulalio A, Behm-Ansmant I, Schweizer D, Izaurralde E (2007) P-body formation is a consequence, not the cause, of RNA-mediated gene silencing. Mol Cell Biol 27:3970-3981
        doi: 10.1128/MCB.00128-07

    37. Finnen RL, Pangka KR, Banfield BW (2012) Herpes simplex virus 2 infection impacts stress granule accumulation. J Virol 86:8119-8130
        doi: 10.1128/JVI.00313-12

    38. Finnen RL, Hay TJ, Dauber B, Smiley JR, Banfield BW (2014) The herpes simplex virus 2 virion-associated ribonuclease vhs interferes with stress granule formation. J Virol 88:12727-12739
        doi: 10.1128/JVI.01554-14

    39. Finnen RL, Zhu M, Li J, Romo D, Banfield BW (2016) Herpes simplex virus 2 virion host shutoff endoribonuclease activity is required to disrupt stress granule formation. J Virol 90:7943-7955
        doi: 10.1128/JVI.00947-16

    40. Fournier MJ, Coudert L, Mellaoui S, Adjibade P, Gareau C, Cote MF, Sonenberg N, Gaudreault RC, Mazroui R (2013) Inactivation of the mTORC1-eukaryotic translation initiation factor 4E pathway alters stress granule formation. Mol Cell Biol 33:2285-2301
        doi: 10.1128/MCB.01517-12

    41. Fricke J, Koo LY, Brown CR, Collins PL (2013) p38 and OGT sequestration into viral inclusion bodies in cells infected with human respiratory syncytial virus suppresses MK2 activities and stress granule assembly. J Virol 87:1333-1347
        doi: 10.1128/JVI.02263-12

    42. Frolova E, Gorchakov R, Garmashova N, Atasheva S, Vergara LA, Frolov I (2006) Formation of nsP3-specific protein complexes during Sindbis virus replication. J Virol 80:4122-4134
        doi: 10.1128/JVI.80.8.4122-4134.2006

    43. Fujimura K, Sasaki AT, Anderson P (2012) Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules. Nucleic Acids Res 40:8099-8110
        doi: 10.1093/nar/gks566

    44. Fung G, Ng CS, Zhang J, Shi J, Wong J, Piesik P, Han L, Chu F, Jagdeo J, Jan E, Fujita T, Luo H (2013) Production of a dominant-negative fragment due to G3BP1 cleavage contributes to the disruption of mitochondria-associated protective stress granules during CVB3 infection. PLoS ONE 8:e79546
        doi: 10.1371/journal.pone.0079546

    45. Furtak V, Mulky A, Rawlings SA, Kozhaya L, Lee K, Kewalramani VN, Unutmaz D (2010) Perturbation of the P-body component Mov10 inhibits HIV-1 infectivity. PLoS ONE 5:e9081
        doi: 10.1371/journal.pone.0009081

    46. Gallois-Montbrun S, Kramer B, Swanson CM, Byers H, Lynham S, Ward M, Malim MH (2007) Antiviral protein APOBEC3G localizes to ribonucleoprotein complexes found in P bodies and stress granules. J Virol 81:2165-2178
        doi: 10.1128/JVI.02287-06

    47. Garaigorta U, Heim MH, Boyd B, Wieland S, Chisari FV (2012) Hepatitis C virus (HCV) induces formation of stress granules whose proteins regulate HCV RNA replication and virus assembly and egress. J Virol 86:11043-11056
        doi: 10.1128/JVI.07101-11

    48. Garcia MA, Meurs EF, Esteban M (2007) The dsRNA protein kinase PKR: virus and cell control. Biochimie 89:799-811
        doi: 10.1016/j.biochi.2007.03.001

    49. Gilks N, Kedersha N, Ayodele M, Shen L, Stoecklin G, Dember LM, Anderson P (2004) Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol Biol Cell 15:5383-5398
        doi: 10.1091/mbc.e04-08-0715

    50. Gorchakov R, Garmashova N, Frolova E, Frolov I (2008) Different types of nsP3-containing protein complexes in Sindbis virus-infected cells. J Virol 82:10088-10101
        doi: 10.1128/JVI.01011-08

    51. Greer AE, Hearing P, Ketner G (2011) The adenovirus E4 11 k protein binds and relocalizes the cytoplasmic P-body component Ddx6 to aggresomes. Virology 417:161-168
        doi: 10.1016/j.virol.2011.05.017

    52. Habjan M, Pichlmair A, Elliott RM, Overby AK, Glatter T, Gstaiger M, Superti-Furga G, Unger H, Weber F (2009) NSs protein of rift valley fever virus induces the specific degradation of the double-stranded RNA-dependent protein kinase. J Virol 83:4365-4375
        doi: 10.1128/JVI.02148-08

    53. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000a) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099-1108
        doi: 10.1016/S1097-2765(00)00108-8

    54. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000b) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897-904
        doi: 10.1016/S1097-2765(00)80330-5

    55. Hebner CM, Wilson R, Rader J, Bidder M, Laimins LA (2006) Human papillomaviruses target the double-stranded RNA protein kinase pathway. J Gen Virol 87:3183-3193
        doi: 10.1099/vir.0.82098-0

    56. Heinicke LA, Wong CJ, Lary J, Nallagatla SR, Diegelman-Parente A, Zheng X, Cole JL, Bevilacqua PC (2009) RNA dimerization promotes PKR dimerization and activation. J Mol Biol 390:319-338
        doi: 10.1016/j.jmb.2009.05.005

    57. Heinrich BS, Cureton DK, Rahmeh AA, Whelan SP (2010) Protein expression redirects vesicular stomatitis virus RNA synthesis to cytoplasmic inclusions. PLoS Pathog 6:e1000958
        doi: 10.1371/journal.ppat.1000958

    58. Hoenen T, Shabman RS, Groseth A, Herwig A, Weber M, Schudt G, Dolnik O, Basler CF, Becker S, Feldmann H (2012) Inclusion bodies are a site of ebolavirus replication. J Virol 86:11779-11788
        doi: 10.1128/JVI.01525-12

    59. Hopkins KC, Tartell MA, Herrmann C, Hackett BA, Taschuk F, Panda D, Menghani SV, Sabin LR, Cherry S (2015) Virus-induced translational arrest through 4EBP1/2-dependent decay of 5′-TOP mRNAs restricts viral infection. Proc Natl Acad Sci U S A 112:E2920-2929
        doi: 10.1073/pnas.1418805112

    60. Hou S, Kumar A, Xu Z, Airo AM, Stryapunina I, Wong CP, Branton W, Tchesnokov E, Gotte M, Power C, Hobman TC (2017) Zika virus hijacks stress granule proteins and modulates the host stress response. J Virol.

    61. Hu Z, Wang Y, Tang Q, Yang X, Qin Y, Chen M (2018) Inclusion bodies of human parainfluenza virus type 3 inhibit antiviral stress granule formation by shielding viral RNAs. PLoS Pathog 14:e1006948
        doi: 10.1371/journal.ppat.1006948

    62. Hubstenberger A, Courel M, Benard M, Souquere S, Ernoult-Lange M, Chouaib R, Yi Z, Morlot JB, Munier A, Fradet M, Daunesse M, Bertrand E, Pierron G, Mozziconacci J, Kress M, Weil D (2017) P-Body purification reveals the condensation of repressed mRNA regulons. Mol Cell 68:144-157.e145
        doi: 10.1016/j.molcel.2017.09.003

    63. Humoud MN, Doyle N, Royall E, Willcocks MM, Sorgeloos F, van Kuppeveld F, Roberts LO, Goodfellow IG, Langereis MA, Locker N (2016) Feline calicivirus infection disrupts assembly of cytoplasmic stress granules and induces G3BP1 cleavage. J Virol 90:6489-6501
        doi: 10.1128/JVI.00647-16

    64. Ikegami T, Narayanan K, Won S, Kamitani W, Peters CJ, Makino S (2009) Rift Valley fever virus NSs protein promotes post-transcriptional downregulation of protein kinase PKR and inhibits eIF2alpha phosphorylation. PLoS Pathog 5:e1000287
        doi: 10.1371/journal.ppat.1000287

    65. Ingelfinger D, Arndt-Jovin DJ, Luhrmann R, Achsel T (2002) The human LSm1-7 proteins colocalize with the mRNA-degrading enzymes Dcp1/2 and Xrnl in distinct cytoplasmic foci. RNA 8:1489-1501

    66. Iseni F, Garcin D, Nishio M, Kedersha N, Anderson P, Kolakofsky D (2002) Sendai virus trailer RNA binds TIAR, a cellular protein involved in virus-induced apoptosis. EMBO J 21:5141-5150
        doi: 10.1093/emboj/cdf513

    67. Isler JA, Skalet AH, Alwine JC (2005) Human cytomegalovirus infection activates and regulates the unfolded protein response. J Virol 79:6890-6899
        doi: 10.1128/JVI.79.11.6890-6899.2005

    68. Ivanov PA, Chudinova EM, Nadezhdina ES (2003) Disruption of microtubules inhibits cytoplasmic ribonucleoprotein stress granule formation. Exp Cell Res 290:227-233
        doi: 10.1016/S0014-4827(03)00290-8

    69. Ivanov P, Kedersha N, Anderson P (2018) Stress granules and processing bodies in translational control. Cold Spring Harb Perspect Biol.

    70. Izumi T, Burdick R, Shigemi M, Plisov S, Hu WS, Pathak VK (2013) Mov10 and APOBEC3G localization to processing bodies is not required for virion incorporation and antiviral activity. J Virol 87:11047-11062
        doi: 10.1128/JVI.02070-13

    71. Jackson RJ, Hellen CU, Pestova TV (2010) The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol 11:113-127
        doi: 10.1038/nrm2838

    72. Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A, Parker R (2016) ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164:487-498
        doi: 10.1016/j.cell.2015.12.038

    73. Jayabalan AK, Sanchez A, Park RY, Yoon SP, Kang GY, Baek JH, Anderson P, Kee Y, Ohn T (2016) NEDDylation promotes stress granule assembly. Nat Commun 7:12125
        doi: 10.1038/ncomms12125

    74. Katsafanas GC, Moss B (2007) Colocalization of transcription and translation within cytoplasmic poxvirus factories coordinates viral expression and subjugates host functions. Cell Host Microbe 2:221-228
        doi: 10.1016/j.chom.2007.08.005

    75. Kedersha N, Anderson P (2002) Stress granules: sites of mRNA triage that regulate mRNA stability and translatability. Biochem Soc Trans 30:963-969
        doi: 10.1042/bst0300963

    76. Kedersha NL, Gupta M, Li W, Miller I, Anderson P (1999) RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. J Cell Biol 147:1431-1442
        doi: 10.1083/jcb.147.7.1431

    77. Kedersha N, Cho MR, Li W, Yacono PW, Chen S, Gilks N, Golan DE, Anderson P (2000) Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules. J Cell Biol 151:1257-1268
        doi: 10.1083/jcb.151.6.1257

    78. Kedersha N, Stoecklin G, Ayodele M, Yacono P, Lykke-Andersen J, Fritzler MJ, Scheuner D, Kaufman RJ, Golan DE, Anderson P (2005) Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J Cell Biol 169:871-884
        doi: 10.1083/jcb.200502088

    79. Kedersha N, Tisdale S, Hickman T, Anderson P (2008) Real-time and quantitative imaging of mammalian stress granules and processing bodies. Methods Enzymol 448:521-552
        doi: 10.1016/S0076-6879(08)02626-8

    80. Kedersha N, Ivanov P, Anderson P (2013) Stress granules and cell signaling: more than just a passing phase? Trends Biochem Sci 38:494-506
        doi: 10.1016/j.tibs.2013.07.004

    81. Kedersha N, Panas MD, Achorn CA, Lyons S, Tisdale S, Hickman T, Thomas M, Lieberman J, McInerney GM, Ivanov P, Anderson P (2016) G3BP-Caprin1-USP10 complexes mediate stress granule condensation and associate with 40S subunits. J Cell Biol 212:845-860
        doi: 10.1083/jcb.201508028

    82. Khaperskyy DA, Hatchette TF, McCormick C (2012) Influenza A virus inhibits cytoplasmic stress granule formation. FASEB J 26:1629-1639
        doi: 10.1096/fj.11-196915

    83. Khong A, Jan E (2011) Modulation of stress granules and P bodies during dicistrovirus infection. J Virol 85:1439-1451
        doi: 10.1128/JVI.02220-10

    84. Kojima E, Takeuchi A, Haneda M, Yagi A, Hasegawa T, Yamaki K, Takeda K, Akira S, Shimokata K, Isobe K (2003) The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice. FASEB J 17:1573-1575
        doi: 10.1096/fj.02-1184fje

    85. Lahaye X, Vidy A, Pomier C, Obiang L, Harper F, Gaudin Y, Blondel D (2009) Functional characterization of Negri bodies (NBs) in rabies virus-infected cells: evidence that NBs are sites of viral transcription and replication. J Virol 83:7948-7958
        doi: 10.1128/JVI.00554-09

    86. Le Sage V, Cinti A, McCarthy S, Amorim R, Rao S, Daino GL, Tramontano E, Branch DR, Mouland AJ (2017) Ebola virus VP35 blocks stress granule assembly. Virology 502:73-83
        doi: 10.1016/j.virol.2016.12.012

    87. Leung AK, Vyas S, Rood JE, Bhutkar A, Sharp PA, Chang P (2011) Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol Cell 42:489-499
        doi: 10.1016/j.molcel.2011.04.015

    88. Li W, Li Y, Kedersha N, Anderson P, Emara M, Swiderek KM, Moreno GT, Brinton MA (2002) Cell proteins TIA-1 and TIAR interact with the 3′ stem-loop of the West Nile virus complementary minus-strand RNA and facilitate virus replication. J Virol 76:11989-12000
        doi: 10.1128/JVI.76.23.11989-12000.2002

    89. Li S, Peters GA, Ding K, Zhang X, Qin J, Sen GC (2006) Molecular basis for PKR activation by PACT or dsRNA. Proc Natl Acad Sci U S A 103:10005-10010
        doi: 10.1073/pnas.0602317103

    90. Lindquist ME, Lifland AW, Utley TJ, Santangelo PJ, Crowe JE Jr (2010) Respiratory syncytial virus induces host RNA stress granules to facilitate viral replication. J Virol 84:12274-12284
        doi: 10.1128/JVI.00260-10

    91. Lindquist ME, Mainou BA, Dermody TS, Crowe JE Jr (2011) Activation of protein kinase R is required for induction of stress granules by respiratory syncytial virus but dispensable for viral replication. Virology 413:103-110
        doi: 10.1016/j.virol.2011.02.009

    92. Linero FN, Thomas MG, Boccaccio GL, Scolaro LA (2011) Junin virus infection impairs stress-granule formation in Vero cells treated with arsenite via inhibition of eIF2alpha phosphorylation. J Gen Virol 92:2889-2899
        doi: 10.1099/vir.0.033407-0

    93. Liu R, Moss B (2016) Opposing roles of double-stranded RNA effector pathways and viral defense proteins revealed with CRISPR-Cas9 Knockout cell lines and vaccinia virus mutants. J Virol 90:7864-7879
        doi: 10.1128/JVI.00869-16

    94. Liu J, Valencia-Sanchez MA, Hannon GJ, Parker R (2005) MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat Cell Biol 7:719-723
        doi: 10.1038/ncb1274

    95. Liu TT, Yang Q, Li M, Zhong B, Ran Y, Liu LL, Yang Y, Wang YY, Shu HB (2016) LSm14A plays a critical role in antiviral immune responses by regulating MITA level in a cell-specific manner. J Immunol 196:5101-5111
        doi: 10.4049/jimmunol.1600212

    96. Ma S, Bhattacharjee RB, Bag J (2009) Expression of poly(A)-binding protein is upregulated during recovery from heat shock in HeLa cells. FEBS J 276:552-570
        doi: 10.1111/j.1742-4658.2008.06803.x

    97. Matsuki H, Takahashi M, Higuchi M, Makokha GN, Oie M, Fujii M (2013) Both G3BP1 and G3BP2 contribute to stress granule formation. Genes Cells 18:135-146
        doi: 10.1111/gtc.2013.18.issue-2

    98. Mazroui R, Sukarieh R, Bordeleau ME, Kaufman RJ, Northcote P, Tanaka J, Gallouzi I, Pelletier J (2006) Inhibition of ribosome recruitment induces stress granule formation independently of eukaryotic initiation factor 2alpha phosphorylation. Mol Biol Cell 17:4212-4219
        doi: 10.1091/mbc.e06-04-0318

    99. McCormick C, Khaperskyy DA (2017) Translation inhibition and stress granules in the antiviral immune response. Nat Rev Immunol 17:647-660
        doi: 10.1038/nri.2017.63

    100. McEwen E, Kedersha N, Song B, Scheuner D, Gilks N, Han A, Chen JJ, Anderson P, Kaufman RJ (2005) Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. J Biol Chem 280:16925-16933
        doi: 10.1074/jbc.M412882200

    101. McInerney GM, Kedersha NL, Kaufman RJ, Anderson P, Liljestrom P (2005) Importance of eIF2alpha phosphorylation and stress granule assembly in alphavirus translation regulation. Mol Biol Cell 16:3753-3763
        doi: 10.1091/mbc.e05-02-0124

    102. Meng X, Xiang Y (2019) RNA granules associated with SAMD9-mediated poxvirus restriction are similar to antiviral granules in composition but do not require TIA1 for poxvirus restriction. Virology 529:16-22
        doi: 10.1016/j.virol.2019.01.007

    103. Mir MA, Duran WA, Hjelle BL, Ye C, Panganiban AT (2008) Storage of cellular 5′ mRNA caps in P bodies for viral cap-snatching. Proc Natl Acad Sci U S A 105:19294-19299
        doi: 10.1073/pnas.0807211105

    104. Mok BW, Song W, Wang P, Tai H, Chen Y, Zheng M, Wen X, Lau SY, Wu WL, Matsumoto K, Yuen KY, Chen H (2012) The NS1 protein of influenza A virus interacts with cellular processing bodies and stress granules through RNA-associated protein 55 (RAP55) during virus infection. J Virol 86:12695-12707
        doi: 10.1128/JVI.00647-12

    105. Montero H, Rojas M, Arias CF, Lopez S (2008) Rotavirus infection induces the phosphorylation of eIF2alpha but prevents the formation of stress granules. J Virol 82:1496-1504
        doi: 10.1128/JVI.01779-07

    106. Nakagawa K, Narayanan K, Wada M, Makino S (2018) Inhibition of stress granule formation by middle east respiratory syndrome coronavirus 4a accessory protein facilitates viral translation, leading to efficient virus replication. J Virol 92:e00902-18

    107. Nallagatla SR, Hwang J, Toroney R, Zheng X, Cameron CE, Bevilacqua PC (2007) 5′-triphosphate-dependent activation of PKR by RNAs with short stem-loops. Science 318:1455-1458
        doi: 10.1126/science.1147347

    108. Nathans R, Chu CY, Serquina AK, Lu CC, Cao H, Rana TM (2009) Cellular microRNA and P bodies modulate host-HIV-1 interactions. Mol Cell 34:696-709
        doi: 10.1016/j.molcel.2009.06.003

    109. Nelson EV, Schmidt KM, Deflube LR, Doganay S, Banadyga L, Olejnik J, Hume AJ, Ryabchikova E, Ebihara H, Kedersha N, Ha T, Muhlberger E (2016) Ebola virus does not induce stress granule formation during infection and sequesters stress granule proteins within viral inclusions. J Virol 90:7268-7284
        doi: 10.1128/JVI.00459-16

    110. Ng CS, Jogi M, Yoo JS, Onomoto K, Koike S, Iwasaki T, Yoneyama M, Kato H, Fujita T (2013) Encephalomyocarditis virus disrupts stress granules, the critical platform for triggering antiviral innate immune responses. J Virol 87:9511-9522
        doi: 10.1128/JVI.03248-12

    111. Nikolic J, Civas A, Lama Z (2016) Rabies virus infection induces the formation of stress granules closely connected to the viral factories. PLoS Pathog 12:e1005942
        doi: 10.1371/journal.ppat.1005942

    112. Oceguera A, Peralta AV, Martinez-Delgado G, Arias CF, Lopez S (2018) Rotavirus RNAs sponge host cell RNA binding proteins and interfere with their subcellular localization. Virology 525:96-105
        doi: 10.1016/j.virol.2018.09.013

    113. Okonski KM, Samuel CE (2013) Stress granule formation induced by measles virus is protein kinase PKR dependent and impaired by RNA adenosine deaminase ADAR1. J Virol 87:756-766
        doi: 10.1128/JVI.02270-12

    114. Onomoto K, Jogi M, Yoo JS, Narita R, Morimoto S, Takemura A, Sambhara S, Kawaguchi A, Osari S, Nagata K, Matsumiya T, Namiki H, Yoneyama M, Fujita T (2012) Critical role of an antiviral stress granule containing RIG-I and PKR in viral detection and innate immunity. PLoS ONE 7:e43031
        doi: 10.1371/journal.pone.0043031

    115. Panas MD, Ivanov P, Anderson P (2016) Mechanistic insights into mammalian stress granule dynamics. J Cell Biol 215:313-323
        doi: 10.1083/jcb.201609081

    116. Patel CV, Handy I, Goldsmith T, Patel RC (2000) PACT, a stress-modulated cellular activator of interferon-induced double-stranded RNA-activated protein kinase, PKR. J Biol Chem 275:37993-37998
        doi: 10.1074/jbc.M004762200

    117. Pene V, Li Q, Sodroski C, Hsu CS, Liang TJ (2015) Dynamic interaction of stress granules, DDX3X, and IKK-alpha mediates multiple functions in hepatitis C virus infection. J Virol 89:5462-5477
        doi: 10.1128/JVI.03197-14

    118. Poblete-Duran N, Prades-Perez Y, Vera-Otarola J, Soto-Rifo R, Valiente-Echeverria F (2016) Who regulates whom? an overview of RNA granules and viral infections. Viruses 8:E180
        doi: 10.3390/v8070180

    119. Protter DSW, Parker R (2016) Principles and properties of stress granules. Trends Cell Biol 26:668-679
        doi: 10.1016/j.tcb.2016.05.004

    120. Rabouw HH, Langereis MA, Knaap RC, Dalebout TJ (2016) Middle east respiratory coronavirus accessory protein 4a inhibits PKR-mediated antiviral stress responses. PLoS Pathog 12:e1005982
        doi: 10.1371/journal.ppat.1005982

    121. Reed JC, Molter B, Geary CD, McNevin J, McElrath J, Giri S, Klein KC, Lingappa JR (2012) HIV-1 Gag co-opts a cellular complex containing DDX6, a helicase that facilitates capsid assembly. J Cell Biol 198:439-456
        doi: 10.1083/jcb.201111012

    122. Reineke LC, Kedersha N, Langereis MA, van Kuppeveld FJ, Lloyd RE (2015) Stress granules regulate double-stranded RNA-dependent protein kinase activation through a complex containing G3BP1 and Caprin1. MBio 6:e02486

    123. Rincheval V, Lelek M, Gault E, Bouillier C, Sitterlin D, Blouquit-Laye S, Galloux M, Zimmer C, Eleouet JF, Rameix-Welti MA (2017) Functional organization of cytoplasmic inclusion bodies in cells infected by respiratory syncytial virus. Nat Commun 8:563
        doi: 10.1038/s41467-017-00655-9

    124. Rojas M, Arias CF, Lopez S (2010) Protein kinase R is responsible for the phosphorylation of eIF2alpha in rotavirus infection. J Virol 84:10457-10466
        doi: 10.1128/JVI.00625-10

    125. Rozelle DK, Filone CM, Kedersha N, Connor JH (2014) Activation of stress response pathways promotes formation of antiviral granules and restricts virus replication. Mol Cell Biol 34:2003-2016
        doi: 10.1128/MCB.01630-13

    126. Ruggieri A, Dazert E, Metz P, Hofmann S, Bergeest JP, Mazur J, Bankhead P, Hiet MS, Kallis S, Alvisi G, Samuel CE, Lohmann V, Kaderali L, Rohr K, Frese M, Stoecklin G, Bartenschlager R (2012) Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection. Cell Host Microbe 12:71-85
        doi: 10.1016/j.chom.2012.05.013

    127. Sciortino MT, Parisi T, Siracusano G, Mastino A, Taddeo B, Roizman B (2013) The virion host shutoff RNase plays a key role in blocking the activation of protein kinase R in cells infected with herpes simplex virus 1. J Virol 87:3271-3276
        doi: 10.1128/JVI.03049-12

    128. Sen GL, Blau HM (2005) Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies. Nat Cell Biol 7:633-636
        doi: 10.1038/ncb1265

    129. Seto E, Inoue T, Nakatani Y, Yamada M, Isomura H (2014) Processing bodies accumulate in human cytomegalovirus-infected cells and do not affect viral replication at high multiplicity of infection. Virology 458-459:151-161
        doi: 10.1016/j.virol.2014.04.022

    130. Sharma NR, Majerciak V, Kruhlak MJ, Zheng ZM (2017) KSHV inhibits stress granule formation by viral ORF57 blocking PKR activation. PLoS Pathog 13:e1006677
        doi: 10.1371/journal.ppat.1006677

    131. Sheth U, Parker R (2006) Targeting of aberrant mRNAs to cytoplasmic processing bodies. Cell 125:1095-1109
        doi: 10.1016/j.cell.2006.04.037

    132. Silva PA, Pereira CF, Dalebout TJ, Spaan WJ, Bredenbeek PJ (2010) An RNA pseudoknot is required for production of yellow fever virus subgenomic RNA by the host nuclease XRN1. J Virol 84:11395-11406
        doi: 10.1128/JVI.01047-10

    133. Simpson-Holley M, Kedersha N, Dower K, Rubins KH, Anderson P, Hensley LE, Connor JH (2011) Formation of antiviral cytoplasmic granules during orthopoxvirus infection. J Virol 85:1581-1593
        doi: 10.1128/JVI.02247-10

    134. Sivan G, Glushakow-Smith SG, Katsafanas GC, Americo JL, Moss B (2018) Human host range restriction of the vaccinia virus C7/K1 double deletion mutant is mediated by an atypical mode of translation inhibition. J Virol 92:e01329-18

    135. Smith RW, Gray NK (2010) Poly(A)-binding protein (PABP): a common viral target. Biochem J 426:1-12
        doi: 10.1042/BJ20091571

    136. Sokoloski KJ, Dickson AM, Chaskey EL, Garneau NL, Wilusz CJ, Wilusz J (2010) Sindbis virus usurps the cellular HuR protein to stabilize its transcripts and promote productive infections in mammalian and mosquito cells. Cell Host Microbe 8:196-207
        doi: 10.1016/j.chom.2010.07.003

    137. Srivastava SP, Kumar KU, Kaufman RJ (1998) Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase. J Biol Chem 273:2416-2423
        doi: 10.1074/jbc.273.4.2416

    138. Stoecklin G, Kedersha N (2013) Relationship of GW/P-bodies with stress granules. Adv Exp Med Biol 768:197-211
        doi: 10.1007/978-1-4614-5107-5

    139. Stohr N, Lederer M, Reinke C, Meyer S, Hatzfeld M, Singer RH, Huttelmaier S (2006) ZBP1 regulates mRNA stability during cellular stress. J Cell Biol 175:527-534
        doi: 10.1083/jcb.200608071

    140. Takeuchi K, Komatsu T, Kitagawa Y, Sada K, Gotoh B (2008) Sendai virus C protein plays a role in restricting PKR activation by limiting the generation of intracellular double-stranded RNA. J Virol 82:10102-10110
        doi: 10.1128/JVI.00599-08

    141. Thomas MG, Loschi M, Desbats MA, Boccaccio GL (2011) RNA granules: the good, the bad and the ugly. Cell Signal 23:324-334
        doi: 10.1016/j.cellsig.2010.08.011

    142. Toroney R, Nallagatla SR, Boyer JA, Cameron CE, Bevilacqua PC (2010) Regulation of PKR by HCV IRES RNA: importance of domain Ⅱ and NS5A. J Mol Biol 400:393-412
        doi: 10.1016/j.jmb.2010.04.059

    143. Tourriere H, Chebli K, Zekri L, Courselaud B, Blanchard JM, Bertrand E, Tazi J (2003) The RasGAP-associated endoribonuclease G3BP assembles stress granules. J Cell Biol 160:823-831
        doi: 10.1083/jcb.200212128

    144. Tsai WC, Gayatri S, Reineke LC, Sbardella G, Bedford MT, Lloyd RE (2016) Arginine demethylation of G3BP1 promotes stress granule assembly. J Biol Chem 291:22671-22685
        doi: 10.1074/jbc.M116.739573

    145. Tu YC, Yu CY, Liang JJ, Lin E, Liao CL, Lin YL (2012) Blocking double-stranded RNA-activated protein kinase PKR by Japanese encephalitis virus nonstructural protein 2A. J Virol 86:10347-10358
        doi: 10.1128/JVI.00525-12

    146. Visser LJ, Medina GN, Rabouw HH, de Groot RJ, Langereis MA, de Los T, van Kuppeveld FJM (2019) Foot-and-mouth disease virus leader protease cleaves G3BP1 and G3BP2 and inhibits stress granule formation. J Virol 93:e00922-18

    147. von der Haar T, Gross JD, Wagner G, McCarthy JE (2004) The mRNA cap-binding protein eIF4E in post-transcriptional gene expression. Nat Struct Mol Biol 11:503-511
        doi: 10.1038/nsmb779

    148. Wang T, Tian C, Zhang W, Luo K, Sarkis PT, Yu L, Liu B, Yu Y, Yu XF (2007) 7SL RNA mediates virion packaging of the antiviral cytidine deaminase APOBEC3G. J Virol 81:13112-13124
        doi: 10.1128/JVI.00892-07

    149. Ward AM, Bidet K, Yinglin A, Ler SG, Hogue K, Blackstock W, Gunaratne J, Garcia-Blanco MA (2011) Quantitative mass spectrometry of DENV-2 RNA-interacting proteins reveals that the DEAD-box RNA helicase DDX6 binds the DB1 and DB2 3′ UTR structures. RNA Biol 8:1173-1186
        doi: 10.4161/rna.8.6.17836

    150. Wek SA, Zhu S, Wek RC (1995) The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids. Mol Cell Biol 15:4497-4506
        doi: 10.1128/MCB.15.8.4497

    151. Wheeler JR, Matheny T, Jain S, Abrisch R, Parker R (2016) Distinct stages in stress granule assembly and disassembly. Elife 5:e18413
        doi: 10.7554/eLife.18413

    152. White JP, Lloyd RE (2012) Regulation of stress granules in virus systems. Trends Microbiol 20:175-183
        doi: 10.1016/j.tim.2012.02.001

    153. White JP, Cardenas AM, Marissen WE, Lloyd RE (2007) Inhibition of cytoplasmic mRNA stress granule formation by a viral proteinase. Cell Host Microbe 2:295-305
        doi: 10.1016/j.chom.2007.08.006

    154. Wichroski MJ, Robb GB, Rana TM (2006) Human retroviral host restriction factors APOBEC3G and APOBEC3F localize to mRNA processing bodies. PLoS Pathog 2:e41
        doi: 10.1371/journal.ppat.0020041

    155. Wilczynska A, Aigueperse C, Kress M, Dautry F, Weil D (2005) The translational regulator CPEB1 provides a link between dcp1 bodies and stress granules. J Cell Sci 118:981-992
        doi: 10.1242/jcs.01692

    156. Willis KL, Langland JO, Shisler JL (2011) Viral double-stranded RNAs from vaccinia virus early or intermediate gene transcripts possess PKR activating function, resulting in NF-kappaB activation, when the K1 protein is absent or mutated. J Biol Chem 286:7765-7778
        doi: 10.1074/jbc.M110.194704

    157. Xia J, Chen X, Xu F, Wang Y, Shi Y, Li Y, He J, Zhang P (2015) Dengue virus infection induces formation of G3BP1 granules in human lung epithelial cells. Arch Virol 160:2991-2999
        doi: 10.1007/s00705-015-2578-9

    158. Yang X, Hu Z, Fan S, Zhang Q, Zhong Y, Guo D, Qin Y, Chen M (2018) Picornavirus 2A protease regulates stress granule formation to facilitate viral translation. PLoS Pathog 14:e1006901
        doi: 10.1371/journal.ppat.1006901

    159. Ye X, Pan T, Wang D, Fang L, Ma J, Zhu X, Shi Y, Zhang K, Zheng H, Chen H, Li K, Xiao S (2018) Foot-and-mouth disease virus counteracts on internal ribosome entry site suppression by G3BP1 and Inhibits G3BP1-mediated stress granule assembly via post-translational mechanisms. Front Immunol 9:1142
        doi: 10.3389/fimmu.2018.01142

    160. Youn JY, Dunham WH, Hong SJ, Knight JDR, Bashkurov M, Chen GI, Bagci H, Rathod B, MacLeod G, Eng SWM, Angers S, Morris Q, Fabian M, Cote JF, Gingras AC (2018) High-density proximity mapping reveals the subcellular organization of mRNA-associated granules and bodies. Mol Cell 69:517-532.e511
        doi: 10.1016/j.molcel.2017.12.020

    161. Yu JH, Yang WH, Gulick T, Bloch KD, Bloch DB (2005) Ge-1 is a central component of the mammalian cytoplasmic mRNA processing body. RNA 11:1795-1802
        doi: 10.1261/rna.2142405

    162. Zaborowska I, Kellner K, Henry M, Meleady P, Walsh D (2012) Recruitment of host translation initiation factor eIF4G by the vaccinia virus ssDNA-binding protein I3. Virology 425:11-22
        doi: 10.1016/j.virol.2011.12.022

    163. Ziehr B, Vincent HA, Moorman NJ (2016) Human cytomegalovirus pTRS1 and pIRS1 antagonize protein kinase R To facilitate virus replication. J Virol 90:3839-3848
        doi: 10.1128/JVI.02714-15

    164. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21-35
        doi: 10.1038/nrm3025

  • 加载中

Figures(4) / Tables(3)

Article Metrics

Article views(87) PDF downloads(6) Cited by()

Proportional views
    通讯作者: 陈斌,
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Viral Regulation of RNA Granules in Infected Cells

      Corresponding author: Zhi-Ming Zheng,
      Corresponding author: Mingzhou Chen,
    • 1. State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan 430072, China
    • 2. Tumor Virus RNA Biology Section, RNA Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA

    Abstract: RNA granules are cytoplasmic, microscopically visible, non-membrane ribo-nucleoprotein structures and are important posttranscriptional regulators in gene expression by controlling RNA translation and stability. TIA/G3BP/PABP-specific stress granules (SG) and GW182/DCP-specific RNA processing bodies (PB) are two major distinguishable RNA granules in somatic cells and contain various ribosomal subunits, translation factors, scaffold proteins, RNA-binding proteins, RNA decay enzymes and helicases to exclude mRNAs from the cellular active translational pool. Although SG formation is inducible due to cellular stress, PB exist physiologically in every cell. Both RNA granules are important components of the host antiviral defense. Virus infection imposes stress on host cells and thus induces SG formation. However, both RNA and DNA viruses must confront the hostile environment of host innate immunity and apply various strategies to block the formation of SG and PB for their effective infection and multiplication. This review summarizes the current research development in the field and the mechanisms of how individual viruses suppress the formation of host SG and PB for virus production.

    • While the intracellular environment and embedded cellular machinery provide the needed vital force and necessary materials for viruses to replicate after infection, these host machineries are not available to these foreign invaders at ease. In fact, viruses have to counter the multiple layers of intracellular defense to replicate and establish their dominance for their propagation. RNA granules (Thomas et al.2011) are dynamic non-membrane subcellular structures (Ivanov et al.2018) containing translationally silenced messenger ribonucleoproteins (mRNPs), which play an important role in regulation of cellular homeostasis, RNA metabolism and gene expression at the posttranscriptional level (Anderson and Kedersha 2009). Stress granules (SG) and processing bodies (PB) (Eulalio et al.2007) are two of RNA granules well characterized in yeast and mammalian cells (Poblete-Duran et al.2016) and are important components of the host cell antiviral defense.

      SG are non-membranous, transiently assembled cytoplasmic aggregates of 48S mRNPs and associated proteins (Stohr et al.2006; Buchan and Parker 2009), where stalled translation preinitiation complexes (PICs) repress the translation of nonessential mRNAs (Anderson et al.2015) and modulate cell signaling by sequestering key signal translation proteins (Kedersha et al.2013). Thus, SG are thought to be the aggregates of stable, translationally silent mRNAs (Kedersha and Anderson 2002). A variety of environmental stresses, including viral infection, can trigger SG formation in eukaryotic cells (Anderson and Kedersha 2008). In contrast, PB can exist in the absence of stress (Stoecklin and Kedersha 2013), which are sites of active mRNA decay (Decker and Parker 2012). SG initiate global translational arrest by storing mRNA (Anderson and Kedersha 2009) for exchange with either polysomes for translation or PB for degradation (Kedersha et al.2005). RNA-binding proteins TIA-1 (Kedersha et al.1999; Gilks et al.2004), G3BP (Tourriere et al.2003; Matsuki et al.2013) and PABP (Ma et al.2009; Smith and Gray 2010; Burgess et al.2011) are three fundamental components of SG during stress (Fig. 1). GW182 and de-capping/de-adenylating enzymes are specific components of PB (Kedersha et al.2005), where siRNA- or miRNA-guided mRNAs are processed and degraded (Liu et al.2005) (Fig. 1). Virus infection imposes stress on host cells (McInerney et al.2005) and thereby induces SG formation. SG can shut off the translation of bulk mRNAs (Poblete-Duran et al.2016) to regulate gene expression and compartmentalization of heterologous viral RNAs and proteins. At the same time, viruses must take strategies to confront these responses and maximize their own replication efficiency (White and Lloyd 2012) by inhibition of SG formation and disruption of PB assembly via virally encoded factors.

      Figure 1.  Mammalian RNA granules. HeLa cells immunostaining with anti-TIA-1 (left and middle, red) show stress granules (SG) during stress of NaAS2O3 (+arsenite, middle) and with anti-GW182 show processing bodies (PB) under physiological condition. Arrows indicate granules (SG or PB)

    • The process of SG formation can be artificially divided into the following steps (Fig. 2): (1) accumulation of stalled translation initiation complexes (Panas et al.2016) in response to various types of stress; (2) the RNA-binding proteins such as RAS-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) and T cell-restricted intracellular antigen 1 (TIA1) bind mRNAs and aggregate to nucleate SG formation. Self-aggregation of G3BP1 (Tourriere et al.2003) and the binding of TIA1 and TIAR (TIA-1-related protein) to polysome-free mRNAs, which exposes prion-like domains (Gilks et al. 2004), trigger mRNP aggregation. The aggregation of proteins is dynamic, and can rapidly exchange between SG and cytosol (Kedersha et al. 2000, 2005). (3) large SG aggregate from smaller foci via posttranslational modification and microtubule transport (McCormick and Khaperskyy 2017). Many SG proteins undergo multiple post-translational modifications (Jayabalan et al.2016; Protter and Parker 2016). For example, G3BP1 must be demethylated (Tsai et al.2016), dephosphorylated (Kedersha et al.2016) and poly(ADP)-ribosylated (Leung et al.2011) to promote SG nucleation. Accordingly, SG formation also requires ongoing transport of mRNPs along with an intact microtubule cytoskeleton (Ivanov et al.2003). Theoretically, viral interference with any of these important steps may modulate SG formation in cells. In fact, many viral factors can interfere with SG formation and/or function. Meanwhile, SG can entrap viral RNA in some cases (McCormick and Khaperskyy 2017). Therefore, SG are thought to be antiviral (Rozelle et al.2014). Thus, to illustrate the relationship between SG and RNA viruses would be important for us to better understand the interactions of host and viruses.

      Figure 2.  Viruses induce SG formation. Type Ⅰ SG formation: RNAs derived from rotavirus, RSV and HCV activate PKR; High levels of glycoproteins produced from enveloped virus activate PERK; HCMV infection activates PERK; Sindbis virus genomic RNA activates GCN2. Type Ⅱ SG formation: RVFV attenuates mTOR signaling to inhibite 4EBP phosphorylation. All above lead to the formation of stalled translation complexes to initiate the assembly of SG

      Up to the present, SG can be divided into two types according to their formation mode. Type Ⅰ SG formation depends on phosphorylation of eukaryotic translation initiation factor-2α (eIF2α) by one of the eIF2 kinases—double-stranded RNA (dsRNA)-activated protein kinase or protein kinase R (PKR) (Srivastava et al.1998; Garcia et al.2007; Onomoto et al.2012), PKR-like ER kinase (PERK) (Harding et al.2000a, b), general control non-derepressible protein 2 (GCN2) (Wek et al.1995; Deng et al.2002) or haeme-regulated inhibitor (HRI) (McEwen et al.2005), which are activated by distinct types of stress. Phosphorylated eIF2α stably binds to eIF2β, which prevents the recycle of eIF2 and regeneration of the eIF2-GTP-Met-tRNAiMet ternary complex. Thus, eIF2α phosphorylation blocks recognition of the initiation codon and joining of the large ribosomal subunit, resulting in accumulation of stalled 48S mRNPs (Jackson et al.2010). Type Ⅱ SG formation is independent of eIF2α phosphorylation, but requires eIF4F complex disruption such as inhibition of eIF4A RNA helicase (Bordeleau et al.2006; Dang et al.2006) or disruption of eIF4E activity (von der Haar et al.2004; Fournier et al.2013) for recognition and binding of RNA cap structure. The stress induced by nutrient, energy, oxygen or growth factor insufficiency inhibits mTOR complex 1 (mTORC1), whose activity is required for the dissociation of 4EBPs from eIF4E (Fujimura et al.2012) and enables eIF4E to form the eIF4F complex, and thus blocks assembly of pre-initiation complexes (Zoncu et al.2011).

      Type Ⅰ SG formation induced by viruses is the most and best-studied example (Table 1, Fig. 3A). Various RNA products derived by viruses including long dsRNA (Rojas et al.2010), 5′-triphosphate RNA (5′-ppp-RNA) (Nallagatla et al.2007), dsRNA that is formed by the antiparallel mRNA transcripts of some DNA viruses (Willis et al.2011), and human immunodeficiency virus (HIV) transactivation-response region (TAR) RNA hairpins (Heinicke et al.2009), can be recognized by PKR. The activated PKR initiates SG assembly through eIF2α phosphorylation. For instance, the persistent phosphorylation of eIF2α (Montero et al.2008) during rotavirus infection is PKR-dependent as a consequence of the accumulation of viral dsRNA in the cytoplasm outside the viroplasms (virus-induced cytoplasmic inclusion bodies called viroplasms [VMs]) (Rojas et al.2010). Even though eIF2α is phosphorylated in rotavirus-infected cells, the formation of SG is prevented and viral proteins are efficiently translated, suggesting that the virus prevents the assembly of these structures presumably downstream of eIF2α phosphorylation to allow the translation of its mRNAs (Mazroui et al.2006). Very recently, Dhillon and Rao found that rotavirus induces formation and sequestration of remodeled SG and PB in the VMs which contain the majorities of their components but selective exclusion of a few proteins (G3BP1 and ZBP1 for SG, DDX6, EDC4 and Pan3 for PB), to promote virus replication (Dhillon and Rao 2018). Oceguera et al. demonstrated that viral RNA of rotavirus could interact with several RNA binding proteins (RBPs) (Xrn1, Dcp1, Ago2, Hur) and interfere with their subcellular localization (Oceguera et al.2018). Lindquist et al. (Lindquist et al.2011) first determined that SG induction by respiratory syncytial virus (RSV) was mediated by PKR-dependent eIF2α phosphorylation. The RSV-mediated SG formation was significantly reduced in PKR-knockdown cells (Lindquist et al.2010). In addition, it has been shown that Hepatitis C virus (HCV) strongly activates PKR via the 5′-untranslated region (UTR) of its genome (Toroney et al.2010), thereby inducing SG. NS1-mutant Influenza virus A (IAV) (Khaperskyy et al.2012; Mok et al.2012; Ng et al.2013) and C protein-deficient Sendai virus (SeV) (Takeuchi et al.2008) lead to significant activation of PKR and eIF2α phosphorylation. Besides, PERK could be activated by high levels of glycoproteins produced from enveloped viruses (Chan and Egan 2005), and general control non-derepressible-2 (GCN2) could be activated by Sindbis virus (SINV) genomic RNA (Berlanga et al.2006), both leading to phosphorylation of eIF2α. GCN2 prevents replication of SINV in the early stages of the viral replicative cycle by blocking the synthesis of NSPs from SINV RNA (Berlanga et al.2006; Frolova et al.2006; Gorchakov et al.2008).

      Table 1.  Regulation of SG by viruses

      Figure 3.  Viruses interfer with SG formation. A Viruses modulate eIF2a phosphorylation. IBs of HPIV3 shield viral RNAs from recognition by PKR; IAV NS1, MERS-CoV accessory protein 4a, EBOV VP35, SeV and MV C protein and KSHV ORF57 prevent viral dsRNA from binding by PKR; ORF57 interacts with PACT to prevent PKR activation; HCMV pTRS1 and pIRS1 and HSV-1 vhs and Us11 block PKR activation; HCV NS5A and JEV NS2A interact with PKR and prevent PKR dimerization; N and GPC of JUNV impair the phosphorylation of eIF2a; HCV modulates GADD34 and PP1 to de-phosphorylate eIF2a. B Viruses modulate SG formation downstream of eIF2a phosphorylation. 3C protease of PV, EMCV, FMDV and CVB3 cleaves G3BP at Q326; FCV NS6 protein cleaves G3BP at E405; 2A protease of EV71, PV and CVA cleaves eIF4G at G689; L protein of both TMEV and mengovirus inhibits G3BP1 aggregation; DENV 30-UTR interacts with G3BP; SeV Trailer RNA captures TIAR from SG; WNV and Dengue virus (DENV) 30-end genome captures TIA-1/TIAR; HSV-2 vhs localizes to SG and its endoribonuclease activity is required to disrupt SG formation; EBOV and RSV sequester SG proteins within viral inclusion bodies; VV sequesters crucial SG components within DNA factories.

      Viruses also induce SG formation independent of eIF2α phosphorylation (Table 1). The most typical example is from Rift Valley fever virus (RVFV) (Habjan et al.2009; Ikegami et al.2009) (Fig. 2). RVFV (Hopkins et al.2015) infection attenuates Akt/mTOR signaling and inhibits 4EBP phosphorylation and translation of 5′-TOP mRNAs, subsequently leading to an inhibition of global protein translation. 5′-TOP-containing mRNAs are indeed targeted to PB, where RVFV uses these cellular mRNAs for cap-snatching (Hopkins et al.2015). This can reflect that SG may interact with PB in a process that is thought to result in the exchange of mRNA cargos (Kedersha et al.2008). Whether any virus induces SG formation to cause translation inhibition due to the destruction of eIF4G or eIF4A is worth exploring in the future.

    • SG formation shuts off bulk host protein synthesis. However, all viruses depend on the host translation apparatus for their gene expression. Therefore, viruses, as intracellular parasites, have to modulate the stress response pathway and SG assembly to translate their proteins for virus replication. RNA viruses modulate stress response pathway at different levels of SG formation (Table 1): One is to regulate eIF2α phosphorylation, and the other is to regulate the process of SG nucleation.

    • In some cases, viral gene products can act as antagonists by targeting the virus-activated eIF2α kinases such as PKR or even by directly modulating the phosphorylation of eIF2α (Fig. 3A). IAV NS1 (Khaperskyy et al.2012; Ng et al.2013), Middle East respiratory syndrome coronavirus (MERS-CoV) accessory protein 4a (Rabouw et al.2016; Nakagawa et al.2018), and Ebola virus (EBOV) multifunctional protein VP35 (Nelson et al.2016; Le Sage et al.2017) bind viral dsRNA and prevent the viral dsRNA from PKR binding to inhibit SG formation. Inhibition of SG formation facilitates the translation of viral mRNAs, leading to efficient virus replication. HCV NS5A protein (Toroney et al.2010) binds to the PKR dimerization domain to inhibit PKR activation. Japanese encephalitis virus (JEV) NS2A protein (Tu et al.2012) might similarly interact with PKR and then prevent PKR dimer formation. SeV (Takeuchi et al.2008) and measles virus (MV) (Okonski and Samuel 2013) encode a C protein to limit the accumulation of dsRNA to inhibit SG formation. It seems that a portion of RNA viruses encode RNA binding proteins to antagonize the activity of PKR. There are also other groups of RNA viruses which directly modulate the phosphorylation of eIF2α without PKR. Junín virus (JUNV) prevents SG assembly by impairing the phosphorylation of eIF2α through its nucleoprotein (N) and glycoprotein precursor (GPC) (Linero et al.2011). However, its mechanism remains to be elucidated, although it may be similar to HCV. Ruggieri and colleagues reported that HCV rapidly de-phosphorylated eIF2α through protein phosphatase 1 (PP1) and its regulatory subunit GADD34 (growth arrest and DNA-damage-inducible 34) (Kojima et al.2003; Clavarino et al.2012; Ruggieri et al.2012).

    • Several RNA viruses have been shown to express viral effectors that can actively disrupt the accumulation of SG through cleavage of SG components (Fig. 3B). Poliovirus (PV) induces SG formation in early phase but induces SG disassembly at later stages via cleavage of G3BP by viral 3C, thus preventing SG formation (White et al.2007). Similar findings were also reported for encephalomyocarditis virus (EMCV) (Ng et al.2013), foot-and-mouth disease virus (FMDV) (Ye et al.2018; Visser et al.2019), coxsackievirus B3 (CBV3) (Fung et al.2013) and feline calicivirus (FCV) (Humoud et al.2016). FCV infection does not cause accumulation of SG, despite an increased phosphorylation of eIF2α (Humoud et al.2016). This is because FCV NS6Pro, a 3C-like proteinase, cleaves G3BP1 at a site different from the poliovirus 3C proteinase. Unlike FCV, murine norovirus (MNV) does not cleave G3BP1 and thus does not inhibit SG formation during virus infection (Humoud et al.2016). In general, picornaviruses inhibit SG formation by viral 2A/L or 3C cleaving the major components of SG. In recent study, Yang et al. found that the 2A protease of picornavirus (EV71, PV, CVA) inhibits typical SG formation, which is PKR and eIF2α phosphorylation-dependent, but induces atypical SG formation by cleaving eIF4GI to sequester cellular mRNA and release viral mRNA, thereby facilitating viral infection (Yang et al.2018). In other words, the 2A protease can transform the overall translation machinery favorable for productive viral infection by induction of atypical SG while blocking the typical SG in the presence of G3BP cleavage by viral 3C protease during viral infection (Yang et al.2018).

      Redistribution or sequestering SG components to the viral replication sites is another strategy used by many viruses to impair SG assembly in infected cells (Fig. 3B). ZIKV infection induces the redistribution of TIAR to the viral RNA replication sites (Hou et al.2017); SeV Trailer RNA captures TIAR from SG (Iseni et al.2002); West Nile Virus (WNV) and Dengue virus (DENV) 3′-end viral genome captures TIA-1/TIAR (Li et al.2002; Emara and Brinton 2007; Xia et al.2015); DENV 3′-UTR interacts with G3BP1, G3BP2, Caprin1 and USP10 (Ward et al.2011; Reineke et al.2015); JEV recruits G3BP and USP10 to the perinuclear region through the interaction of JEV core protein with Caprin-1, a SG-associated cellular factor (Ward et al.2011). Theiler murine encephalomyelitis virus (TMEV) and mengovirus, a strain of EMCV, express the leader (L) protein to inhibit G3BP1 aggregation (Borghese and Michiels 2011). Sequestration or redistribution of SG components by viruses through protein-protein and protein-RNA interactions not only prevents SG assembly, but also facilitates viral genome replication. HCV-JFH1 infection redistributes several SG components, including G3BP1, ataxin-2 (ATX2), and poly(A)-binding protein 1 (PABP1), to the HCV replication complex (RC) (Ariumi et al.2011; Pene et al.2015), and co-opts G3BP1 to mediate efficient viral replication by interaction with NS5B and the 5′ end of the HCV minus-strand RNA (Ariumi et al.2011; Garaigorta et al.2012).

    • Studies on Human parainfluenza virus type 3 (HPIV3) (Hu et al.2018), RSV (Rincheval et al.2017), EBOV (Hoenen et al.2012), Rabies virus (RABV) (Lahaye et al.2009) and Vesicular stomatitis virus (VSV) (Heinrich et al.2010) showed that inclusion bodies (IBs) of negative stranded RNA viruses are the sites of viral RNA synthesis. A recent study suggested an emerging role of IBs in HPIV3 replication by shielding newly synthesized viral RNA from the antiviral effect of SG (Hu et al.2018) (Fig. 3B). Sequestration of O-linked N-acetylglucosamine (OGN) transferase (OGT), an enzyme that catalyzes the posttranslational addition of OGN to protein targets, in RSV IBs was also proposed to regulate SG nucleation and suppression of SG formation (Fricke et al.2013) (Fig. 3B). Viral transcription and replication of RABV take place within Negri bodies (NBs), which are IB-like structures (Lahaye et al.2009). RABV-induced SG are normally located closely to NBs. Viral mRNAs rather than viral genomic RNA accumulate in the SG-like structures together with cellular mRNAs were found to be specially transported from NBs to SG-like structures (Nikolic et al.2016). VSV infection also induces formation of the SG-like structures that co-localize with viral replication proteins and RNA, which are different from canonical SG (Dinh et al.2013). SG proteins (eIF4G, eIF3, PABP) are selectively sequestered within Ebola virus inclusion bodies and co-localize with viral RNA to form inclusion body-bound granules, which are functionally and structurally different from canonical SG, probably leading to inhibit the antiviral role of SG (Nelson et al.2016) (Fig. 3B). Collectively, these findings provoke more investigations on the roles of viral IBs in viral replication and resisting cellular responses.

    • Unlike RNA viruses, the regulation of SG formation during infection with DNA viruses is poorly understood. It was reported that human cytomegalovirus (HCMV) infection modifies the unfolded protein response (UPR) and activates PERK (Fig. 2), but limiting the amount of phosphorylated eIF2α to maintain translation (Isler et al.2005). Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 (Sharma et al.2017) interacts with PKR and PKR-activating protein (PACT) (Patel et al.2000) to inhibit PKR binding dsRNA and prevent PACT-PKR interaction in the PKR pathway (Li et al.2006), respectively. HCMV pTRS1 and pIRS1 antagonize PKR to facilitate virus replication (Ziehr et al.2016). The HSV-1 vhs (Sciortino et al.2013) and Us11 protein (Cassady and Gross 2002) play a key role in blocking the activation of PKR. Smiley and colleagues also demonstrated that infection with virion host shutoff protein (vhs)-defective herpes simplex virus 1 (HSV-1) triggers SG formation, and PKR is essential for SG formation in the absence of vhs (Dauber et al.2016) (Fig. 3A). Finnen et al. previously established that herpes simplex virus 2 (HSV-2) infection impacts stress granule accumulation in response to oxidative stress (Finnen et al.2012). They also demonstrated that disruption of SG is mediated by vhs (Finnen et al.2014), whose endoribonuclease activity is required to disrupt SG formation (Finnen et al.2016). HSV-2 vhs indeed have the ability to localize to SG (Finnen et al.2016) (Fig. 3B). This implies that removal of RNA from SG promotes its disassembly and that intact RNA is crucial for maintaining SG structure. It will be interesting to test the function of endoribonucleases in SG disassembly. Vaccinia virus (VV) sequesters crucial translation initiation factors, such as G3BP1, Caprin1, eIF4E, PABP and eIF4G (Katsafanas and Moss 2007; Simpson-Holley et al.2011; Zaborowska et al.2012), within cytoplasmic viral DNA factories to utilize SG components for different purposes (Fig. 3B). A recent study (Meng and Xiang 2019) suggested that the RNA granules are resulted from untranslated mRNA accumulation in viral DNA factories (Liu and Moss 2016) and TIA-1 is probably not required for granule formation and anti-poxviruses. Instead, the granules formation is most likely driven by an array of RNA-protein interactions and requires no specific SG components (Sivan et al.2018; Meng and Xiang 2019).

    • PB were first reported in the scientific literature by Bashkirov et al.1997, and described as "small granules or discrete, prominent foci" or as the cytoplasmic location of the mouse exoribonuclease mXrn1p (Bashkirov et al.1997). Like SG, PB lack outer lipid membrane and now are recognized to be the sites where non-translating mRNAs accumulate for different fates including decay, storage, or returning to translation. A variety of enzymes involved in mRNA deadenylation (Ccr1, Caf1, Not1) (Sheth and Parker 2006), decapping (Dcp1/2, Lsm1-7, Edc3proteins) (Ingelfinger et al.2002; Yu et al.2005), nonsense-mediated decay (NMD) proteins (SMG5-6-7, UPF1) (Ingelfinger et al.2002; Durand et al.2007), in addition to scaffolding proteins (Ge-1/Hedls) (Yu et al.2005) and translation control factors (CPEB, eIF4E-T) (Andrei et al.2005; Wilczynska et al.2005), are the components of PB and used as routine markers to distinguish these granules. Nonetheless, some components (APOBEC3G, BRF1, DDX3, FAST, TTP, Rap55) (McEwen et al.2005; Sen and Blau 2005; Gallois-Montbrun et al.2007; Chen et al.2008) have also been shown to be shared by both SG and PB, suggesting a substantial linkage of these two structures and movement of mRNAs between both RNA granules. Interestingly, among these components, PB also include RNA-induced silencing complex (RISC) or miRNA associated argonaute (Ago) proteins (also shared with SG) and the GW182 protein which provides scaffolding activities for RISC to function, suggesting PB being the sites of miRNA mediated translation repression. The scaffolding activity of GW182 is critical for PB and knockdown of GW182 expression disrupts PB formation (Liu et al.2005). Notably, GW182 has been shown to bind to Ago2 which is critical for miRNA function and PB formation (Liu et al.2005). Recent evidence indicates that GW182 can recruit up to three molecules of Ago2 via its three GW motifs (glycine-tryptophan repeats) while each Ago protein has a single GW182-binding site (Elkayam et al.2017) (Fig. 4).

      Figure 4.  Disruption of PB assembly by viruses. The mRNA translation can be stopped for various reasons including the binding of miRNA. The translating mRNA can be stripped of ribosomes and the initiation complex can be collaps when binding to miRNA-RISC complex. The mRNPs targeted by PB components undergo three outcomes: 1. Translational inhibition; 2. Pan2/3-mediated deadenylation; 3. RNA decay by other associated RNA decay factors (e.g., Xrn1, Dcp1a, DDX6, and Lsm). Several RNA and DNA viruses which inhibit PB assembly are shown

      By applying fluorescence-activated particle sorting to purify PB in combination with mass spectrometry, Hubstenberger et al. identified 125 proteins that are significantly associated with PB (Hubstenberger et al.2017). By labeling several PB-localized proteins with a BirA (E. coli biotin ligase) enzyme in combination with mass spectrometry after streptavidin pulldown, Youn et al. identified 38 proteins in the PB (Youn et al.2018). ISGs (interferon stimulated genes) can also be found in PB during virus infection (Hebner et al.2006).

    • In comparison to viral regulation of SG, interaction of virus and PB was not much explored. It is an assumption that RNA viruses must regulate RNA decay processes/machinery to prevent degradation of virus genomes and mRNAs. Recently, some progress has been made to understand the relationship between PB components and some viruses in the context of viral gene expression. The data in published literatures are summarized in (Table 2). Mutation induced in the PB core components to affect the viral life cycles are well studied and tabulated in an earlier review (Beckham et al.2007). The report linking the assembly of yeast Ty3 retrotransposons virus—like particles with PB presented the first link between human retrovirus and PB (Checkley et al.2010). The later study revealed PB to be the site of anti-viral host factors APOBEC3G and APOBEC3F (A3G or A3F, apolipoprotein B mRNA-editing enzyme catalytic polypeptide 1-like) family of cytidine de-aminases, presumably representing a component of innate immunity against HIV (Wichroski et al.2006; Gallois-Montbrun et al.2007). In a different study, A3F was found to specifically interact with cellular signal recognition particle RNA (7SL RNA). Efficient packaging of 7SL RNA and A3F into HIV virons was mediated by the RNA-binding nucleocapsid domain of HIV-1 Gag (Wang et al.2007).

      Table 2.  Regulation of PB assembly by viruses

      The bona fide and unique dependence of viruses on PB came from the studies on plant brome mosaic virus (BMV) (Beckham et al.2007). This study suggested the accumulation of BMV mRNAs in PB was an important step in RNA replication complex assembly for BMV, and possibly for other positive-strand RNA viruses. Nonetheless, many RNA viruses initiate the process of transcription of viral RNA by the process of 'cap snatching' which involves the acquisition of capped 5′ oligonucleotides from cellular mRNAs. Interestingly, PB were shown to serve as a pool of primers in the case of Hantavirus while its nucleocapsid protein, which accumulates in PB, binds 5′ caps with high affinity (Mir et al.2008).

      The base-pair complementarity between a miRNA and a target mRNA dictates the miRNA to specifically repress posttranscriptional expression of mRNAs. Subsequent events in this process involve relocation of RNA-induced silencing complexes (RISCs) together with several other RNA binding proteins to form PB. In this context, HIV-1 mRNA interacts with RISC proteins and disrupting PB structures enhances viral production and infectivity, suggesting a role of PB against viral infection (Nathans et al.2009). Specific miR-29a-HIV-1 mRNA interaction was found to enhance viral mRNA association with RISC and PB proteins and regulate HIV-1 production and infectivity. HIV Nef interacts with Ago2 via its glycine-tryptophan region and functions as a viral suppressor of RNAi (Aqil et al.2013). While overexpression of Mov10, a component of PB and an ATP-dependent 5′-3′ RNA helicase, inhibits HIV production (Burdick et al.2010; Furtak et al.2010), Mov10 and APOBEC3G localization to PB is not required for HIV virion incorporation and antiviral activity (Izumi et al.2013). It becomes clear that Mov10 inhibits virus infection by enhancing RIG-I-MAVS-Independent IFN Induction (Cuevas et al.2016) and stabilizing A3G from degradation (Chen et al.2017).

      The anticipated evidence of viral disruption of PB also came from the study with poliovirus (PV), a plus-strand RNA virus showing that PB are disrupted during PV infection in cells by 4 h post infection (Dougherty et al.2011). This function is attributed to viral proteinase 3C which degrades several components of PB including Xrn1 and Dcp1a, but not affecting others such as GW182, Edc3 and Edc4. Rotaviruses disassemble PB by using viral RNA as a sponge for RNA binding proteins to redistribute several PB components, including Ago2, GW182 and Dcp1 PB (Oceguera et al.2018). In fact, rotavirus disrupts PB through multiple mechanisms. The viral NSP1 protein seems to degrade PB component Pan3, while relocalizing other two components (Xrn1 and Dcp1a) (Bhowmick et al.2015). Intriguingly, exclusion of SG and PB components from the viroplasm is important for rotavirus replication and progeny virus production (Dhillon and Rao 2018).

    • While RNA viruses have evolved to co-opt or modulate the assembly of PB, this effect is rather unclear during infection by DNA viruses. Since most of the DNA viruses replicate and assemble in the nucleus, therefore as proposed for RNA viruses, accumulation of viral RNAs in PB for assembly cannot be a strategy required by DNA viruses. However, the close relationship of PB with translational repression reasonably provides a foundation for PB being antiviral cellular components against DNA viruses. Thus it is assumed that those factories suppressing mRNA translation would inhibit protein production of DNA viruses. To fight back, the DNA viruses have to develope strategies to bypass this antagonism mediated by PB for their survival and productive infection (Table 2).

      Adenovirus E4 11 k, the product of E4 ORF3, accumulates viral late mRNA transcripts and at least five proteins of PB (Rck/p54/DDX6, Ago2, xrn1, Ge1, and Lsm-1) in the E4 11 k-induced cytoplasmic aggresomes. Redistribution of the PB components to the aggresomes, not to the PB, leads to inactivate or destroy these proteins. E4 11 k protein interacts with RNA helicase DDX6, one of the PB proteins, for its redistribution. Because PB are the sites for mRNA degradation, their alteration by E4 11 k suggests a role of E4 11 k in viral late mRNA accumulation (Greer et al.2011).

      The role of PB in regulation of cytomegalovirus infection remains elusive. First, HCMV infection does not affect, but rather accumulates the formation of PB; second, PB formed during HCMV infection do not contain Ago2; third, HCMV prevents viral IE1 mRNA, a major IE gene product to encode a critical protein for viral gene expression and replication, from colocalization with PB (Seto et al.2014).

      By generating a transgenic mice deficient of PB component LSm14A (or Rap55), recent studies showed that LSm14A plays a critical and specific role in the induction of antiviral cytokines (IFN-β, IFN-α, and IL-6) in dendritic cells (DCs). DNA viruses (HSV-1 and murine herpesvirus 68) and RNA virus VSV trigger this induction, but Sendai virus lacks such an effect (Anderson and Kedersha 2009; Liu et al.2016). LSm14A deficiency specifically downregulates MITA/STING (stimulator of interferon genes) level in DCs by impairing its nuclear mRNA precursor processing. In contrast to its role in mRNA decay, this study revealed a role of LSm14 in nuclear mRNA precursor processing and cell-specific regulatory mechanism of antiviral immune responses (Liu et al.2016).

      KSHV kaposin B, a latent protein linked with cancer progression, induces PB dispersion (Corcoran et al.2015). Kaposin B activates the stress-responsive kinase MK2 in endothelial cells (ECs) to selectively block the decay of AU-rich mRNAs (ARE-mRNAs) which encode pro-inflammatory cytokines and angiogenic factors and to reprogram ECs through post-transcriptional control of EC gene expression and secretion. KSHV ORF57 protein inhibits the formation of PB during lytic infection by disrupting the essential interaction of Ago2 with GW182 (unpublished data). These data provide the first evidence that a tumor virus RNA-binding protein ORF57 antagonizes the RNA regulatory pathway of host antiviral defenses during lytic infection.

    • SG are highly dynamic structures (Jain et al.2016), which constantly exchange their components to regulate gene expression and are thought to be antiviral. SG composition appears to vary according to the inducing stimulus (Table 3). It's clear that SG assembly/disassembly is a tightly regulated process which accompanies rearrangements of RNA and proteins (Wheeler et al.2016). Although significant advances have been made to understand how viruses regulate SG formation, our current knowledge is not suffucient to fully elucidate the machanism how SG are regulated in living cells. Further works are needed to address the following questions: First, is there any pathway to be a target for antiviral drug development? Second, do SG function as platforms that potentiate virus recognition? Third, is any unexplored pathway leading to SG formation which could be visualized by fluorescence in situ hybridization techniques—including single molecule RNA tracking methods in combination with super-resolution microscopy? Using viruses as a research tool will definitely teach us how the host fights virus infections and how the viruses get away from its host resistance.

      Table 3.  Viruses and SG components

      PB affect viral infections in multiple ways. Thus, it is difficult to generalize a common viral strategy in a particular virus group to interact with the components of PB. The noticed evidence is that viruses in the same family may show extremely distant behavior when they come to interact with PB (Table 2). More studies on virus interactions with PB will be required to characterize the PB to be proviral or antiviral in a context-dependent manner. Other key questions in the field for future studies are: (1) to understand the mechanisms that regulate PB formation in cells. Viral manipulation of PB may provide a better platform to understand this regulation; (2) to determine which viral RNA species preferentially travel through these RNA granules and which ones do not? (3) to identify the RNA elements dictating viral RNA to escape from SG and PB. Thus, discovery of virus regulations of PB assembly represents a new paradigm of virus-host interactions.

    • This work was supported by grants from the China Natural Science Foundation (81825015 and 31630086), the Natural Science Foundation of Hubei Province Innovation Group (2017CFA022), and Intramural Research Program of NCI/NIH (1ZIASC010357 to ZMZ).

    • The authors declare that they have no conflict of interest.

    • This article does not contain any studies with human or animal subjects performed by any of the authors.

    • This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

    Figure (4)  Table (3) Reference (164) Relative (20)



    DownLoad:  Full-Size Img  PowerPoint