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Selective Degradation of Host RNA Polymerase II Transcripts by Influenza A Virus PA-X Host Shutoff Protein

DOI: 10.1371/journal.ppat.1005427

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Abstract:

Influenza A viruses (IAVs) inhibit host gene expression by a process known as host shutoff. Host shutoff limits host innate immune responses and may also redirect the translation apparatus to the production of viral proteins. Multiple IAV proteins regulate host shutoff, including PA-X, a ribonuclease that remains incompletely characterized. We report that PA-X selectively targets host RNA polymerase II (Pol II) transcribed mRNAs, while sparing products of Pol I and Pol III. Interestingly, we show that PA-X can also target Pol II-transcribed RNAs in the nucleus, including non-coding RNAs that are not destined to be translated, and reporter transcripts with RNA hairpin structures that block ribosome loading. Transcript degradation likely occurs in the nucleus, as PA-X is enriched in the nucleus and its nuclear localization correlates with reduction in target RNA levels. Complete degradation of host mRNAs following PA-X-mediated endonucleolytic cleavage is dependent on the host 5’->3’-exonuclease Xrn1. IAV mRNAs are structurally similar to host mRNAs, but are synthesized and modified at the 3’ end by the action of the viral RNA-dependent RNA polymerase complex. Infection of cells with wild-type IAV or a recombinant PA-X-deficient virus revealed that IAV mRNAs resist PA-X-mediated degradation during infection. At the same time, loss of PA-X resulted in changes in the synthesis of select viral mRNAs and a decrease in viral protein accumulation. Collectively, these results significantly advance our understanding of IAV host shutoff, and suggest that the PA-X causes selective degradation of host mRNAs by discriminating some aspect of Pol II-dependent RNA biogenesis in the nucleus.

 References

[1]  Garfinkel MS, Katze MG. Translational control by influenza virus. Selective and cap-dependent translation of viral mRNAs in infected cells. J Biol Chem. 1992;267: 9383–9390. pmid:1577765
[2]  Nemeroff ME, Barabino SM, Li Y, Keller W, Krug RM. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3’end formation of cellular pre-mRNAs. Mol Cell. 1998;1: 991–1000. pmid:9651582 doi: 10.1016/s1097-2765(00)80099-4
[3]  Rodriguez A, Pérez-González A, Nieto A. Influenza virus infection causes specific degradation of the largest subunit of cellular RNA polymerase II. J Virol. 2007;81: 5315–5324. doi: 10.1128/JVI.02129-06. pmid:17344288
[4]  Twu KY, Kuo R-L, Marklund J, Krug RM. The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in mammalian cells. J Virol. 2007;81: 8112–8121. doi: 10.1128/JVI.00006-07. pmid:17522219
[5]  Jagger BW, Wise HM, Kash JC, Walters K-A, Wills NM, Xiao Y-L, et al. An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response. Science. 2012;337: 199–204. doi: 10.1126/science.1222213. pmid:22745253
[6]  Kwong AD, Frenkel N. Herpes simplex virus-infected cells contain a function(s) that destabilizes both host and viral mRNAs. Proc Natl Acad Sci U S A. 1987;84: 1926–1930. pmid:3031658 doi: 10.1073/pnas.84.7.1926
[7]  Rowe M, Glaunsinger B, van Leeuwen D, Zuo J, Sweetman D, Ganem D, et al. Host shutoff during productive Epstein-Barr virus infection is mediated by BGLF5 and may contribute to immune evasion. Proc Natl Acad Sci U S A. 2007;104: 3366–3371. doi: 10.1073/pnas.0611128104. pmid:17360652
[8]  Glaunsinger B, Ganem D. Lytic KSHV infection inhibits host gene expression by accelerating global mRNA turnover. Mol Cell. 2004;13: 713–723. pmid:15023341 doi: 10.1016/s1097-2765(04)00091-7
[9]  Kamitani W, Narayanan K, Huang C, Lokugamage K, Ikegami T, Ito N, et al. Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation. Proc Natl Acad Sci U S A. 2006;103: 12885–12890. doi: 10.1073/pnas.0603144103. pmid:16912115
[10]  Esclatine A, Taddeo B, Evans L, Roizman B. The herpes simplex virus 1 UL41 gene-dependent destabilization of cellular RNAs is selective and may be sequence-specific. Proc Natl Acad Sci U S A. 2004;101: 3603–3608. doi: 10.1073/pnas.0400354101. pmid:14993598
[11]  Esclatine A, Taddeo B, Roizman B. The UL41 protein of herpes simplex virus mediates selective stabilization or degradation of cellular mRNAs. Proc Natl Acad Sci U S A. 2004;101: 18165–18170. doi: 10.1073/pnas.0408272102. pmid:15596716
[12]  Glaunsinger B, Ganem D. Highly selective escape from KSHV-mediated host mRNA shutoff and its implications for viral pathogenesis. J Exp Med. 2004;200: 391–398. doi: 10.1084/jem.20031881. pmid:15289507
[13]  Clyde K, Glaunsinger BA. Deep Sequencing Reveals Direct Targets of Gammaherpesvirus-Induced mRNA Decay and Suggests That Multiple Mechanisms Govern Cellular Transcript Escape. Means RE, editor. PLoS ONE. 2011;6: e19655. doi: 10.1371/journal.pone.0019655. pmid:21573023
[14]  Gaglia MM, Covarrubias S, Wong W, Glaunsinger BA. A Common Strategy for Host RNA Degradation by Divergent Viruses. J Virol. 2012;86: 9527–9530. doi: 10.1128/JVI.01230-12. pmid:22740404
[15]  Gaglia MM, Rycroft CH, Glaunsinger BA. Transcriptome-Wide Cleavage Site Mapping on Cellular mRNAs Reveals Features Underlying Sequence-Specific Cleavage by the Viral Ribonuclease SOX. PLoS Pathog. 2015;11: e1005305. doi: 10.1371/journal.ppat.1005305. pmid:26646420
[16]  Hu J, Mo Y, Wang X, Gu M, Hu Z, Zhong L, et al. PA-X decreases the pathogenicity of highly pathogenic H5N1 influenza A virus in avian species by inhibiting virus replication and host response. J Virol. 2015;89: 4126–4142. doi: 10.1128/JVI.02132-14. pmid:25631083
[17]  Gao H, Sun Y, Hu J, Qi L, Wang J, Xiong X, et al. The contribution of PA-X to the virulence of pandemic 2009 H1N1 and highly pathogenic H5N1 avian influenza viruses. Sci Rep. 2015;5: 8262. doi: 10.1038/srep08262. pmid:25652161
[18]  Gao H, Xu G, Sun Y, Qi L, Wang J, Kong W, et al. PA-X is a virulence factor in avian H9N2 influenza virus. J Gen Virol. 2015;96: 2587–2594. doi: 10.1099/jgv.0.000232. pmid:26296365
[19]  Hayashi T, MacDonald LA, Takimoto T. Influenza A Virus Protein PA-X Contributes to Viral Growth and Suppression of the Host Antiviral and Immune Responses. J Virol. 2015;89: 6442–6452. doi: 10.1128/JVI.00319-15. pmid:25855745
[20]  Firth AE, Jagger BW, Wise HM, Nelson CC, Parsawar K, Wills NM, et al. Ribosomal frameshifting used in influenza A virus expression occurs within the sequence UCC_UUU_CGU and is in the +1 direction. Open Biol. 2012;2: 120109. doi: 10.1098/rsob.120109. pmid:23155484
[21]  Shi M, Jagger BW, Wise HM, Digard P, Holmes EC, Taubenberger JK. Evolutionary Conservation of the PA-X Open Reading Frame in Segment 3 of Influenza A Virus. J Virol. 2012;86: 12411–12413. doi: 10.1128/JVI.01677-12. pmid:22951836
[22]  Kamitani W, Huang C, Narayanan K, Lokugamage KG, Makino S. A two-pronged strategy to suppress host protein synthesis by SARS coronavirus Nsp1 protein. Nat Struct Mol Biol. 2009;16: 1134–1140. doi: 10.1038/nsmb.1680. pmid:19838190
[23]  Read GS, Frenkel N. Herpes simplex virus mutants defective in the virion-associated shutoff of host polypeptide synthesis and exhibiting abnormal synthesis of alpha (immediate early) viral polypeptides. J Virol. 1983;46: 498–512. pmid:6302315
[24]  Dias A, Bouvier D, Crépin T, McCarthy AA, Hart DJ, Baudin F, et al. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature. 2009;458: 914–918. doi: 10.1038/nature07745. pmid:19194459
[25]  Yuan P, Bartlam M, Lou Z, Chen S, Zhou J, He X, et al. Crystal structure of an avian influenza polymerase PAN reveals an endonuclease active site. Nature. 2009;458: 909–913. doi: 10.1038/nature07720. pmid:19194458
[26]  Bagnéris C, Briggs LC, Savva R, Ebrahimi B, Barrett TE. Crystal structure of a KSHV-SOX-DNA complex: insights into the molecular mechanisms underlying DNase activity and host shutoff. Nucleic Acids Res. 2011;39: 5744–5756. doi: 10.1093/nar/gkr111. pmid:21421561
[27]  Buisson M, Géoui T, Flot D, Tarbouriech N, Ressing ME, Wiertz EJ, et al. A bridge crosses the active-site canyon of the Epstein-Barr virus nuclease with DNase and RNase activities. J Mol Biol. 2009;391: 717–728. doi: 10.1016/j.jmb.2009.06.034. pmid:19538972
[28]  Dahlroth S-L, Gurmu D, Schmitzberger F, Engman H, Haas J, Erlandsen H, et al. Crystal structure of the shutoff and exonuclease protein from the oncogenic Kaposi’s sarcoma-associated herpesvirus. FEBS J. 2009;276: 6636–6645. doi: 10.1111/j.1742-4658.2009.07374.x. pmid:19843164
[29]  Covarrubias S, Gaglia MM, Kumar GR, Wong W, Jackson AO, Glaunsinger BA. Coordinated Destruction of Cellular Messages in Translation Complexes by the Gammaherpesvirus Host Shutoff Factor and the Mammalian Exonuclease Xrn1. Renne R, editor. PLoS Pathog. 2011;7: e1002339. doi: 10.1371/journal.ppat.1002339. pmid:22046136
[30]  Feng P, Everly DN, Read GS. mRNA decay during herpesvirus infections: interaction between a putative viral nuclease and a cellular translation factor. J Virol. 2001;75: 10272–10280. doi: 10.1128/JVI.75.21.10272-10280.2001. pmid:11581395
[31]  Doepker RC, Hsu W-L, Saffran HA, Smiley JR. Herpes simplex virus virion host shutoff protein is stimulated by translation initiation factors eIF4B and eIF4H. J Virol. 2004;78: 4684–4699. pmid:15078951 doi: 10.1128/jvi.78.9.4684-4699.2004
[32]  Plotch SJ, Bouloy M, Ulmanen I, Krug RM. A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription. Cell. 1981;23: 847–858. pmid:6261960 doi: 10.1016/0092-8674(81)90449-9
[33]  Poon LL, Pritlove DC, Fodor E, Brownlee GG. Direct evidence that the poly(A) tail of influenza A virus mRNA is synthesized by reiterative copying of a U track in the virion RNA template. J Virol. 1999;73: 3473–3476. pmid:10074205
[34]  Oishi K, Yamayoshi S, Kawaoka Y. Mapping of a Region of the PA-X Protein of Influenza A Virus That Is Important for Its Shutoff Activity. J Virol. 2015;89: 8661–8665. doi: 10.1128/JVI.01132-15. pmid:26041295
[35]  Hara K, Schmidt FI, Crow M, Brownlee GG. Amino acid residues in the N-terminal region of the PA subunit of influenza A virus RNA polymerase play a critical role in protein stability, endonuclease activity, cap binding, and virion RNA promoter binding. J Virol. 2006;80: 7789–7798. doi: 10.1128/JVI.00600-06. pmid:16873236
[36]  Pijlman GP, Funk A, Kondratieva N, Leung J, Torres S, van der Aa L, et al. A highly structured, nuclease-resistant, noncoding RNA produced by flaviviruses is required for pathogenicity. Cell Host Microbe. 2008;4: 579–591. doi: 10.1016/j.chom.2008.10.007. pmid:19064258
[37]  Elgadi MM, Hayes CE, Smiley JR. The Herpes Simplex Virus vhs Protein Induces Endoribonucleolytic Cleavage of Target RNAs in Cell Extracts. J Virol. 1999;73: 7153–7164. pmid:10438802
[38]  Bavagnoli L, Cucuzza S, Campanini G, Rovida F, Paolucci S, Baldanti F, et al. The novel influenza A virus protein PA-X and its naturally deleted variant show different enzymatic properties in comparison to the viral endonuclease PA. Nucleic Acids Res. 2015; doi: 10.1093/nar/gkv926.
[39]  Kozak M. Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs. Mol Cell Biol. 1989;9: 5134–5142. pmid:2601712 doi: 10.1128/mcb.9.11.5134
[40]  Silverman JL, Sharma S, Cairns TM, Heldwein EE. Fusion-Deficient Insertion Mutants of Herpes Simplex Virus Type 1 Glycoprotein B Adopt the Trimeric Postfusion Conformation. J Virol. 2010;84: 2001–2012. doi: 10.1128/JVI.01791-09. pmid:19939928
[41]  Khaperskyy DA, Emara MM, Johnston BP, Anderson P, Hatchette TF, McCormick C. Influenza a virus host shutoff disables antiviral stress-induced translation arrest. PLoS Pathog. 2014;10: e1004217. doi: 10.1371/journal.ppat.1004217. pmid:25010204
[42]  Krieg PA, Melton DA. Formation of the 3’ end of histone mRNA by post-transcriptional processing. Nature. 1984;308: 203–206. pmid:6700722 doi: 10.1038/308203a0
[43]  Wilusz JE, Freier SM, Spector DL. 3’ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell. 2008;135: 919–932. doi: 10.1016/j.cell.2008.10.012. pmid:19041754
[44]  Uguen P, Murphy S. The 3’ ends of human pre-snRNAs are produced by RNA polymerase II CTD-dependent RNA processing. EMBO J. 2003;22: 4544–4554. doi: 10.1093/emboj/cdg430. pmid:12941705
[45]  Lee YJ, Glaunsinger BA. Aberrant herpesvirus-induced polyadenylation correlates with cellular messenger RNA destruction. PLoS Biol. 2009;7: e1000107. doi: 10.1371/journal.pbio.1000107. pmid:19468299
[46]  Huang C, Lokugamage KG, Rozovics JM, Narayanan K, Semler BL, Makino S. SARS coronavirus nsp1 protein induces template-dependent endonucleolytic cleavage of mRNAs: viral mRNAs are resistant to nsp1-induced RNA cleavage. PLoS Pathog. 2011;7: e1002433. doi: 10.1371/journal.ppat.1002433. pmid:22174690
[47]  Hutin S, Lee Y, Glaunsinger BA. An RNA Element in Human Interleukin 6 Confers Escape from Degradation by the Gammaherpesvirus SOX Protein. J Virol. 2013;87: 4672–4682. doi: 10.1128/JVI.00159-13. pmid:23408619
[48]  Muller M, Hutin S, Marigold O, Li KH, Burlingame A, Glaunsinger BA. A ribonucleoprotein complex protects the interleukin-6 mRNA from degradation by distinct herpesviral endonucleases. PLoS Pathog. 2015;11: e1004899. doi: 10.1371/journal.ppat.1004899. pmid:25965334
[49]  Lee K-M, Tarn W-Y. Coupling pre-mRNA processing to transcription on the RNA factory assembly line. RNA Biol. 2013;10: 380–390. doi: 10.4161/rna.23697. pmid:23392244
[50]  Desmet EA, Bussey KA, Stone R, Takimoto T. Identification of the N-Terminal Domain of the Influenza Virus PA Responsible for the Suppression of Host Protein Synthesis. J Virol. 2013;87: 3108–3118. doi: 10.1128/JVI.02826-12. pmid:23283952
[51]  Gao H, Sun H, Hu J, Qi L, Wang J, Xiong X, et al. The 20 amino acids at the C-terminus of PA-X are associated with increased influenza A virus replication and pathogenicity. J Gen Virol. 2015; doi: 10.1099/vir.0.000143.
[52]  Kolev NG, Steitz JA. Symplekin and multiple other polyadenylation factors participate in 3’-end maturation of histone mRNAs. Genes Dev. 2005;19: 2583–2592. doi: 10.1101/gad.1371105. pmid:16230528
[53]  Dominski Z, Yang X, Marzluff WF. The polyadenylation factor CPSF-73 is involved in histone-pre-mRNA processing. Cell. 2005;123: 37–48. doi: 10.1016/j.cell.2005.08.002. pmid:16213211
[54]  Zhang H, Rigo F, Martinson HG. Poly(A) Signal-Dependent Transcription Termination Occurs through a Conformational Change Mechanism that Does Not Require Cleavage at the Poly(A) Site. Mol Cell. 2015;59: 437–448. doi: 10.1016/j.molcel.2015.06.008. pmid:26166703
[55]  Abernathy E, Clyde K, Yeasmin R, Krug LT, Burlingame A, Coscoy L, et al. Gammaherpesviral gene expression and virion composition are broadly controlled by accelerated mRNA degradation. PLoS Pathog. 2014;10: e1003882. doi: 10.1371/journal.ppat.1003882. pmid:24453974
[56]  Dauber B, Saffran HA, Smiley JR. The herpes simplex virus 1 virion host shutoff protein enhances translation of viral late mRNAs by preventing mRNA overload. J Virol. 2014;88: 9624–9632. doi: 10.1128/JVI.01350-14. pmid:24920814
[57]  Zheng M, Wang P, Song W, Lau S-Y, Liu S, Huang X, et al. A14U Substitution in 3’ Non-Coding Region of M vRNA Supports Replication of NS1-Deleted Influenza Virus by Modulating Alternative Splicing of M mRNAs. J Virol. 2015; doi: 10.1128/JVI.00919-15.
[58]  Roberts KL, Leser GP, Ma C, Lamb RA. The Amphipathic Helix of Influenza A Virus M2 Protein Is Required for Filamentous Bud Formation and Scission of Filamentous and Spherical Particles. J Virol. 2013;87: 9973–9982. doi: 10.1128/JVI.01363-13. pmid:23843641
[59]  Khaperskyy DA, Hatchette TF, McCormick C. Influenza A virus inhibits cytoplasmic stress granule formation. FASEB J Off Publ Fed Am Soc Exp Biol. 2012;26: 1629–1639. doi: 10.1096/fj.11-196915.
[60]  Corcoran JA, Khaperskyy DA, McCormick C. Assays for monitoring viral manipulation of host ARE-mRNA turnover. Methods San Diego Calif. 2011;55: 172–181. doi: 10.1016/j.ymeth.2011.08.005
[61]  Hoffmann E, Neumann G, Kawaoka Y, Hobom G, Webster RG. A DNA transfection system for generation of influenza A virus from eight plasmids. Proc Natl Acad Sci U S A. 2000;97: 6108–6113. doi: 10.1073/pnas.100133697. pmid:10801978
[62]  Kedersha N, Anderson P. Mammalian stress granules and processing bodies. Methods Enzymol. 2007;431: 61–81. pmid:17923231 doi: 10.1016/s0076-6879(07)31005-7
[63]  Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9: 671–675. pmid:22930834 doi: 10.1038/nmeth.2089
[64]  Hoffmann E, Stech J, Guan Y, Webster RG, Perez DR. Universal primer set for the full-length amplification of all influenza A viruses. Arch Virol. 2001;146: 2275–2289. pmid:11811679 doi: 10.1007/s007050170002
[65]  Sei E, Wang T, Hunter OV, Xie Y, Conrad NK. HITS-CLIP analysis uncovers a link between the Kaposi’s sarcoma-associated herpesvirus ORF57 protein and host pre-mRNA metabolism. PLoS Pathog. 2015;11: e1004652. doi: 10.1371/journal.ppat.1004652. pmid:25710169
[66]  Rahim MN, Selman M, Sauder PJ, Forbes NE, Stecho W, Xu W, et al. Generation and characterization of a new panel of broadly reactive anti-NS1 mAbs for detection of influenza A virus. J Gen Virol. 2013;94: 593–605. doi: 10.1099/vir.0.046649-0. pmid:23223621

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