RNA-specific Adenosine Deaminase ADAR1 Suppresses Measles Virus-induced Apoptosis and Activation of Protein Kinase PKR
ADAR1 (adenosine deaminase acting on RNA) catalyzes the conversion of adenosine to inosine, a process known as A-to-I editing. Extensive A-to-I editing has been described in viral RNAs isolated from the brains of patients persistently infected with measles virus, although the precise role of ADAR during measles virus infection remains unknown. We generated human HeLa cells stably deficient in ADAR1 (“ADAR1kd cells”) through short hairpin RNA-mediated knockdown, and using these cells, we tested the effect of ADAR1 deficiency on measles virus (MVvac strain) growth and virus-induced cell death. We found that the growth of mutant viruses lacking expression of the viral accessory proteins V and C (Vko and Cko, respectively) was decreased in ADAR1-deficient cells compared with ADAR1-sufficient cells. In addition, apoptosis was enhanced in ADAR1-deficient cells following infection with wild type and Vko virus but not following infection with Cko virus or treatment with tumor necrosis factor-α or staurosporine. Furthermore, in Cko-infected ADAR1-sufficient cells when ADAR1 did not protect against apoptosis, caspase cleavage of the ADAR1 p150 protein was detected. Finally, enhanced apoptosis in ADAR1kd cells following infection with wild type and Vko virus correlated with enhanced activation of PKR kinase and interferon regulatory factor IRF-3. Taken together, these results demonstrate that ADAR1 is a proviral, antiapoptotic host factor in the context of measles virus infection and suggest that the antiapoptotic activity of ADAR1 is achieved through suppression of activation of proapoptotic and double-stranded RNA-dependent activities, as exemplified by PKR and IRF-3. ADAR1 (adenosine deaminase acting on RNA) catalyzes the conversion of adenosine to inosine, a process known as A-to-I editing. Extensive A-to-I editing has been described in viral RNAs isolated from the brains of patients persistently infected with measles virus, although the precise role of ADAR during measles virus infection remains unknown. We generated human HeLa cells stably deficient in ADAR1 (“ADAR1kd cells”) through short hairpin RNA-mediated knockdown, and using these cells, we tested the effect of ADAR1 deficiency on measles virus (MVvac strain) growth and virus-induced cell death. We found that the growth of mutant viruses lacking expression of the viral accessory proteins V and C (Vko and Cko, respectively) was decreased in ADAR1-deficient cells compared with ADAR1-sufficient cells. In addition, apoptosis was enhanced in ADAR1-deficient cells following infection with wild type and Vko virus but not following infection with Cko virus or treatment with tumor necrosis factor-α or staurosporine. Furthermore, in Cko-infected ADAR1-sufficient cells when ADAR1 did not protect against apoptosis, caspase cleavage of the ADAR1 p150 protein was detected. Finally, enhanced apoptosis in ADAR1kd cells following infection with wild type and Vko virus correlated with enhanced activation of PKR kinase and interferon regulatory factor IRF-3. Taken together, these results demonstrate that ADAR1 is a proviral, antiapoptotic host factor in the context of measles virus infection and suggest that the antiapoptotic activity of ADAR1 is achieved through suppression of activation of proapoptotic and double-stranded RNA-dependent activities, as exemplified by PKR and IRF-3. ADAR1 (adenosine deaminase acting on RNA) is an RNA-specific C-6 adenosine deaminase that catalyzes the conversion of adenosine (A) to inosine (I) on RNAs with double-stranded character (1Toth A.M. Zhang P. Das S. George C.X. Samuel C.E. Prog. Nucleic Acid Res. Mol. Biol. 2006; 81: 369-434Crossref PubMed Scopus (76) Google Scholar, 2Samuel C.E. Clin. Microbiol. Rev. 2001; 14: 778-809Crossref PubMed Scopus (2202) Google Scholar). Such “A-to-I editing” by ADAR1 is of broad biologic importance, because I is recognized as G instead of A by ribosomes and polymerases (2Samuel C.E. Clin. Microbiol. Rev. 2001; 14: 778-809Crossref PubMed Scopus (2202) Google Scholar, 3Bass B.L. Annu. Rev. Biochem. 2002; 71: 817-846Crossref PubMed Scopus (998) Google Scholar). For example, ADAR1 plays an important role in the nervous system, where site-specific editing of glutamate receptor and serotonin-2C receptor pre-mRNAs changes their coding capacity, thereby leading to neurotransmitter receptor protein products with altered physiological properties (4Seeburg P.H. Hartner J. Curr. Opin. Neurobiol. 2003; 13: 279-283Crossref PubMed Scopus (162) Google Scholar, 5Liu Y. Samuel C.E. J. Biol. Chem. 1999; 274: 5070-5077Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 6Liu Y. Emeson R.B. Samuel C.E. J. Biol. Chem. 1999; 274: 18351-18358Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). In addition, ADAR1 is involved in the RNA interference pathway and is known to alter both the targeting and the processing of microRNAs (7Yang W. Chendrimada T.P. Wang Q. Higuchi M. Seeburg P.H. Shiekhattar R. Nishikura K. Nat. Struct. Mol. Biol. 2006; 13: 13-21Crossref PubMed Scopus (623) Google Scholar, 8Kawahara Y. Zinshteyn B. 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The domain structure of the ADAR1 protein product includes the C-terminal deaminase catalytic domain, three centrally located dsRNA 2The abbreviations used are: dsRNAdouble-stranded RNAADAR1kdADAR1 knockdown cellsCkoC knockout measles virusCONkdcontrol knockdown cellseIF-2αeukaryotic translation initiation factor-2αIFNinterferonMTS3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazoliumMVmeasles virusPARPpoly(ADP-ribose) polymerasePKRkdPKR knockdown cellsshRNAshort hairpin RNASSPEsubacute sclerosing panencephalitisTCID5050% tissue culture infectious doseTNF-αtumor necrosis factor-αVkoV knockout measles virusWTwild typeGFPgreen fluorescent proteinzbenzyloxycarbonylfmkfluoromethylketone. binding domains, and one or two N-terminal Z-DNA binding domains (18Patterson J.B. Samuel C.E. Mol. Cell. Biol. 1995; 15: 5376-5388Crossref PubMed Scopus (458) Google Scholar, 19Herbert A. Alfken J. Kim Y.G. Mian I.S. Nishikura K. Rich A. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 8421-8426Crossref PubMed Scopus (280) Google Scholar, 20Kim U. Wang Y. Sanford T. Zeng Y. Nishikura K. Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 11457-11461Crossref PubMed Scopus (383) Google Scholar). Two size forms of the ADAR1 protein are known (18Patterson J.B. Samuel C.E. Mol. Cell. Biol. 1995; 15: 5376-5388Crossref PubMed Scopus (458) Google Scholar, 21Patterson J.B. Thomis D.C. Hans S.L. Samuel C.E. Virology. 1995; 210: 508-511Crossref PubMed Scopus (138) Google Scholar, 22George C.X. Samuel C.E. Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 4621-4626Crossref PubMed Scopus (243) Google Scholar). One, p110, is constitutively expressed and found predominantly in the nucleus of cells; the other, p150, is interferon (IFN)-inducible and is found in both the nucleus and the cytoplasm. Compared with p110, the p150 form of human ADAR1 possesses an additional 295 N-terminal amino acids. The function of the N-terminal extension of p150 is not entirely understood, but the region contains a nuclear export signal (23Poulsen H. Nilsson J. Damgaard C.K. Egebjerg J. Kjems J. Mol. Cell. Biol. 2001; 21: 7862-7871Crossref PubMed Scopus (131) Google Scholar) and an additional Z-DNA binding domain (19Herbert A. Alfken J. Kim Y.G. Mian I.S. Nishikura K. Rich A. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 8421-8426Crossref PubMed Scopus (280) Google Scholar). Because of its regulation by IFN and cytoplasmic localization, the p150 version of ADAR1 is thought to be the form responsible for the A-to-I editing of viral RNAs produced by viruses that replicate in the cytoplasm of infected cells (2Samuel C.E. Clin. Microbiol. Rev. 2001; 14: 778-809Crossref PubMed Scopus (2202) Google Scholar, 3Bass B.L. Annu. Rev. Biochem. 2002; 71: 817-846Crossref PubMed Scopus (998) Google Scholar). double-stranded RNA ADAR1 knockdown cells C knockout measles virus control knockdown cells eukaryotic translation initiation factor-2α interferon 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium measles virus poly(ADP-ribose) polymerase PKR knockdown cells short hairpin RNA subacute sclerosing panencephalitis 50% tissue culture infectious dose tumor necrosis factor-α V knockout measles virus wild type green fluorescent protein benzyloxycarbonyl fluoromethylketone. Measles virus (MV), a member of the Morbillivirus genus of the family Paramyxoviridae, is a negative-stranded RNA virus whose replication cycle takes place entirely in the host cell cytoplasm (24Griffin D. Fields Virology.in: Howley P. Griffin D. Lamb R. Martin M. Roizman B. Straus S. Lippincott Williams & Wilkins, Philadelphia, PA2007: 1551-1585Google Scholar). MV causes an acute respiratory illness in humans, and despite effective vaccination, MV continues to be a pathogen of major global importance (24Griffin D. Fields Virology.in: Howley P. Griffin D. Lamb R. Martin M. Roizman B. Straus S. Lippincott Williams & Wilkins, Philadelphia, PA2007: 1551-1585Google Scholar). In rare cases, the acute infection can lead to a persistent central nervous system infection, resulting in a chronic and fatal disease known as subacute sclerosing panencephalitis (SSPE) (25Garg R.K. Postgrad. Med. J. 2002; 78: 63-70Crossref PubMed Scopus (231) Google Scholar). Analysis of viral RNA from SSPE autopsies reveals extensive A-to-I hypermutation in the matrix gene and several other virus genes (10Cattaneo R. Schmid A. Eschle D. Baczko K. ter Meulen V. Billeter M.A. Cell. 1988; 55: 255-265Abstract Full Text PDF PubMed Scopus (363) Google Scholar, 26Cattaneo R. Schmid A. Spielhofer P. Kaelin K. Baczko K. ter Meulen V. Pardowitz J. Flanagan S. Rima B.K. Udem S.A. Virology. PubMed Scopus Google Scholar, R. Curr. Opin. 1994; PubMed Scopus Google Scholar), a role for ADAR during MV the of ADAR enzymes on the infectious cycle of MV unknown. the role of ADAR1 during MV infection, we used an knockdown to a human HeLa cell stably deficient in ADAR1 cell was used to the of ADAR1 on virus growth and cell by a MV on the The results with the compared with those of mutant viruses lacking expression of the V or C accessory Because ADAR1 is an and because hypermutation as that in SSPE to be to we that or the V or C of virus, to in the ADAR1kd cells compared with we found the that ADAR1 as a host factor in the context of MV infection and to virus growth and virus-induced cell death. the of ADAR1 of virus growth and suppression of virus-induced cell is with of exemplified by those of PKR kinase by RNA) and regulatory HeLa and cells in with and as described A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar). HeLa cells with the knockdown of PKR P. Samuel C.E. J. Virol. 2007; 81: PubMed Scopus Google Scholar, P. B.L. Samuel C.E. J. Virol. PubMed Scopus Google Scholar) or ADAR1 by RNA interference in the with was the and with with was with the and with the was with a of the virus was The virus, as wild type as as and of virus on the as described A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar, P. von V. W. C. R. Virology. 2007; PubMed Scopus Google Scholar). The with was used for of short hairpin expression to human The human ADAR1 targeting in the region of human ADAR1 (18Patterson J.B. Samuel C.E. Mol. Cell. Biol. 1995; 15: 5376-5388Crossref PubMed Scopus (458) Google Scholar) was using The and with the targeting and the resulting was the using the and by HeLa cells using to the and and in the to the and for the was with for cells with the and in the of isolated and by for ADAR1 protein HeLa cells with the with and in the cells, A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google used as an additional and cells infected a of infection of for the of as by 50% on cells to the A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar, Scopus Google Scholar). cell the and protein as described A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar). by and to and the in in against measles virus proteins described A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar). against ADAR1 was described (18Patterson J.B. Samuel C.E. Mol. Cell. Biol. 1995; 15: 5376-5388Crossref PubMed Scopus (458) Google Scholar). from the used to human PKR and and used to and human poly(ADP-ribose) polymerase The was to the is on the conversion of the by enzymes found in cells. in The following cells infected with or Cko virus or with or as infection or of was by a the was on a the effect of ADAR1 on MV infection, we a HeLa in ADAR1 expression is stably by RNA ADAR1kd cells have of the form and of the p150 form of ADAR1 found in HeLa cells or control cells not and We used the and Vko and Cko of of these viruses a gene of the and is a these viruses can through of C.K. R. Curr. Microbiol. Google Scholar), a receptor expressed on ADAR1-deficient and HeLa cell and PKR protein not or cells with of and of or and was and or The was with cells ADAR1kd cells and cells The results are the with for and ADAR1kd cells with and or and cell using the as the cells with or The the of the and ADAR1 cleavage We the growth of and mutant MV in ADAR1-deficient and ADAR1-sufficient and human cell both and for cells A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar), the signal by was for and Vko but for Cko in HeLa and control cells in ADAR1kd cells, the signal for three viruses was that these viruses in the of the growth of virus, infectious virus on cells. in HeLa cells and control cells A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar), the of the Cko virus was the virus, the of Vko was to the virus with A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar). The of the Vko and Cko in ADAR1kd cells compared with ADAR1-sufficient cells, and results suggest that ADAR1 the growth of measles MV growth in ADAR1-sufficient and ADAR1-deficient cells, we effect infection of ADAR1kd compared with or cells with and Vko virus, as by the in the the was The that the of ADAR1kd cells was decreased compared with the of or cells following infection with and Vko virus the Cko virus was or Vko A and is with in ADAR1-sufficient cells A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar), the cell of Cko, was not enhanced in ADAR1kd cells We that the effect by correlated with cleavage of the caspase and was A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar). We with an to the cell in ADAR1kd ADAR1-sufficient for HeLa cells and control cells A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar), the cleavage was following infection with the Cko virus and with the virus In the ADAR1kd cells compared with the ADAR1-sufficient cells, the cleavage following infection with and Vko virus was apoptosis following infection with Cko virus was not enhanced by the ADAR1 RNA is the for apoptosis in cells, apoptosis is in by PKR A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar), a protein kinase that is binding RNA or Because ADAR1 apoptosis and because ADAR1 dsRNA (18Patterson J.B. Samuel C.E. Mol. Cell. Biol. 1995; 15: 5376-5388Crossref PubMed Scopus (458) Google Scholar) and was on its activity B.L. H. Cell. Full Text PDF PubMed Scopus Google Scholar, Cell. Full Text PDF PubMed Scopus Google Scholar), is that ADAR1 against ADAR1 is a of apoptosis, we tested ADAR1 against cell by two other of an that apoptosis the to caspase A. Science. PubMed Scopus Google Scholar), and a broad kinase and of apoptosis Sci. Full Text PDF PubMed Scopus Google Scholar). and cells with with and cell following treatment was by and The of cells and the of cleavage following treatment with and cells, with that PKR not a role in apoptosis P. Samuel C.E. J. Virol. 2007; 81: PubMed Scopus Google Scholar, T. M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). the of cells and the of cleavage following treatment ADAR1kd and cells A and In addition, cell and cleavage following treatment A and in and ADAR1kd compared with cells. results suggest that PKR and ADAR1 against apoptosis by but not infection with the Cko virus and to a Vko virus and treatment with or we detected an additional protein with ADAR1 and protein and is a product of ADAR1 because was recognized by ADAR1 and was in in the ADAR1kd cells and the of protein correlated with we that was a caspase cleavage product of ADAR1 we used the of ADAR1-sufficient cells with both of the ADAR1 product and the cleavage product with the that the ADAR1 protein was a cleavage We that PKR is infection with Cko virus but not or Vko virus and that activation of PKR correlated with measles virus growth and apoptosis A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar). We the that the enhanced cell and decreased virus growth in ADAR1kd cells was to enhanced PKR we PKR using an against we for cells A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar), of PKR activation detected following infection with the or Vko but PKR activation by Cko virus was by in these cells In the ADAR1kd cells, activation of PKR was for three the and of activation to that of the Cko virus-induced activation in the cells of PKR correlated with activation of as by of on and with decreased expression of viral proteins and Because we enhanced PKR activation in ADAR1kd cells but not ADAR1-sufficient cells infection with and we activation of additional be enhanced in these cells. we is a factor for the of D. Maniatis T. Cell. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). is by C-terminal and following activation to the nucleus and J. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). is by including those that receptor gene cytoplasmic and PKR P. Samuel C.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. S. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, M. T. Rev. PubMed Scopus Google Scholar). infection with the Cko virus, but not the or Vko activation was in ADAR1-sufficient cells as by the of that and to C-terminal of P. Samuel C.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. C. J. Mol. Cell. Biol. PubMed Scopus Google Scholar). In the ADAR1kd cells, was by three of PKR infection with of the three and Cko, was in the ADAR1kd cells to the in results that ADAR1 activation as as PKR activation following MV A-to-I hypermutation in SSPE brains ADAR1 in MV replication (1Toth A.M. Zhang P. Das S. George C.X. Samuel C.E. Prog. Nucleic Acid Res. Mol. Biol. 2006; 81: 369-434Crossref PubMed Scopus (76) Google Scholar, 10Cattaneo R. Schmid A. Eschle D. Baczko K. ter Meulen V. Billeter M.A. Cell. 1988; 55: 255-265Abstract Full Text PDF PubMed Scopus (363) Google Scholar), the role of ADAR1 in measles virus infection has not been the role of ADAR1 during MV infection, we generated a human cell stably deficient in ADAR1 that expressed of ADAR1 protein those of the cell that MV We found that ADAR1 the growth of Vko and Cko virus for the V and C In addition, we that ADAR1 against apoptosis by and Vko but not Cko virus results a and antiapoptotic role of ADAR1 during MV in PKR is and proapoptotic during MV infection A.M. P. R. Samuel C.E. J. Virol. PubMed Scopus Google Scholar). one the we enhanced PKR activation in ADAR1kd compared with ADAR1-sufficient control cells in to infection with and Vko PKR activation in the ADAR1kd cells following infection with and Vko virus correlated with enhanced and decreased viral protein expression translation be responsible for the decreased growth of and Vko viruses in the ADAR1kd cells. translation the decreased growth of the Cko virus in the ADAR1kd cells enhanced PKR was not in these cells following infection with the Cko virus C protein has several in cells, including control of virus and replication B. J. Virology. 2005; PubMed Scopus Google Scholar, C. J. S.A. Virology. 2001; PubMed Scopus Google Scholar) as as and P. R. J. Virol. 78: PubMed Scopus Google Scholar), is that ADAR1 other in the MV replication cycle in to protein results an antiapoptotic activity for ADAR1 in cells are with those with gene to apoptosis in the and in C. A. A.M. Higuchi M. Seeburg P.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Q. M. W. J. Nishikura K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). from are to apoptosis Q. M. W. J. Nishikura K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). we that ADAR1 did not cell by or that ADAR1 is not a of Because ADAR1 is a protein with dsRNA editing and activity (1Toth A.M. Zhang P. Das S. George C.X. Samuel C.E. Prog. Nucleic Acid Res. Mol. Biol. 2006; 81: 369-434Crossref PubMed Scopus (76) Google Scholar, B.L. H. Cell. Full Text PDF PubMed Scopus Google Scholar, Cell. Full Text PDF PubMed Scopus Google Scholar), is that ADAR1 against cell by dsRNA or RNA is be the of apoptosis in the system during in the is to that a a apoptosis in that system, and ADAR1 the activity of RNA through editing (1Toth A.M. Zhang P. Das S. George C.X. Samuel C.E. Prog. Nucleic Acid Res. Mol. Biol. 2006; 81: 369-434Crossref PubMed Scopus (76) Google Scholar, H. Nishikura K. Nat. 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Virol. 2002; PubMed Scopus Google Scholar). with with ADAR1 has a role in the replication of RNA viruses of three RNA RNA that and the RNA delta virus Furthermore, a role for ADAR1 during MV infection is with the of of A-to-I hypermutation in MV from brains of SSPE patients R. Curr. Opin. 1994; PubMed Scopus Google Scholar). is that these of hypermutation in MV are the of of ADAR1 by MV as a replication MV not takes of the of ADAR to as PKR and but has to A-to-I of its RNA by ADAR1 during In we an antiapoptotic and role for ADAR1 during MV infection, and results that these of ADAR1 are achieved through suppression of as PKR and IRF-3. suggest that including ADAR1 as a replication factor by the of ADAR to and