MCMV-mediated Inhibition of the Pro-apoptotic Bak Protein Is Required for Optimal Replication

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Successful replication and transmission of large DNA viruses such as the cytomegaloviruses (CMV) family of viruses depends on the ability to interfere with multiple aspects of the host immune response. Apoptosis functions as a host innate defence mechanism against viral infection, and the capacity to interfere with this process is essential for the replication of many viruses. The Bcl-2 family of proteins are the principle regulators of apoptosis, with two pro-apoptotic members, Bax and Bak, essential for apoptosis to proceed. The m38.5 protein encoded by murine CMV (MCMV) has been identified as Bax-specific inhibitor of apoptosis. Recently, m41.1, a protein product encoded by the m41 open reading frame (ORF) of MCMV, has been shown to inhibit Bak activity in vitro. Here we show that m41.1 is critical for optimal MCMV replication in vivo. Growth of a m41.1 mutant was attenuated in multiple organs, a defect that was not apparent in Bak^−/− mice. Thus, m41.1 promotes MCMV replication by inhibiting Bak-dependent apoptosis during in vivo infection. The results show that Bax and Bak mediate non-redundant functions during MCMV infection and that the virus produces distinct inhibitors for each protein to counter the activity of these proteins.

Vyšlo v časopise: MCMV-mediated Inhibition of the Pro-apoptotic Bak Protein Is Required for Optimal Replication. PLoS Pathog 9(2): e32767. doi:10.1371/journal.ppat.1003192
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003192

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Zdroje

1. Miller-KittrellM, SparerTE (2009) Feeling manipulated: cytomegalovirus immune manipulation. Virol J 6: 4.

2. AndoniouCE, Degli-EspostiMA (2006) Insights into the mechanisms of CMV-mediated interference with cellular apoptosis. Immunol Cell Biol 84: 99–106.

3. AndoniouCE (2010) Suicide watch: how cytomegalovirus interferes with the cell-death pathways of infected cells. Tissue Antigens 76: 1–8.

4. YouleRJ, StrasserA (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9: 47–59.

5. LindstenT, RossAJ, KingA, ZongWX, RathmellJC, et al. (2000) The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol Cell 6: 1389–1399.

6. RathmellJC, LindstenT, ZongWX, CinalliRM, ThompsonCB (2002) Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat Immunol 3: 932–939.

7. WestphalD, DewsonG, CzabotarPE, KluckRM (2011) Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta 1813: 521–531.

8. CuconatiA, WhiteE (2002) Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection. Genes Dev 16: 2465–2478.

9. GoldmacherVS, BartleLM, SkaletskayaA, DionneCA, KedershaNL, et al. (1999) A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2. Proc Natl Acad Sci U S A 96: 12536–12541.

10. BoyaP, CohenI, ZamzamiN, VieiraHL, KroemerG (2002) Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization. Cell Death Differ 9: 465–467.

11. RoumierT, VieiraHL, CastedoM, FerriKF, BoyaP, et al. (2002) The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway. Cell Death Differ 9: 1212–1219.

12. ArnoultD, BartleLM, SkaletskayaA, PoncetD, ZamzamiN, et al. (2004) Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria. Proc Natl Acad Sci USA 101: 7988–7993.

13. PoncetD, LarochetteN, PauleauAL, BoyaP, JalilAA, et al. (2004) An anti-apoptotic viral protein that recruits Bax to mitochondria. J Biol Chem 279: 22605–22614.

14. JurakI, SchumacherU, SimicH, VoigtS, BruneW (2008) Murine cytomegalovirus m38.5 protein inhibits Bax-mediated cell death. J Virol 82: 4812–4822.

15. NorrisKL, YouleRJ (2008) Cytomegalovirus proteins vMIA and m38.5 link mitochondrial morphogenesis to Bcl-2 family proteins. J Virol 82: 6232–6243.

16. ArnoultD, SkaletskayaA, EstaquierJ, DufourC, GoldmacherVS (2008) The murine cytomegalovirus cell death suppressor m38.5 binds Bax and blocks Bax-mediated mitochondrial outer membrane permeabilization. Apoptosis 13: 1100–1110.

17. ManzurM, FlemingP, HuangDC, Degli-EspostiMA, AndoniouCE (2009) Virally mediated inhibition of Bax in leukocytes promotes dissemination of murine cytomegalovirus. Cell Death Differ 16: 312–320.

18. KnudsonCM, TungKS, TourtellotteWG, BrownGA, KorsmeyerSJ (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270: 96–99.

19. CamM, HandkeW, Picard-MaureauM, BruneW (2010) Cytomegaloviruses inhibit Bak- and Bax-mediated apoptosis with two separate viral proteins. Cell Death Differ 17: 655–665.

20. BruneW, NevelsM, ShenkT (2003) Murine cytomegalovirus m41 open reading frame encodes a Golgi-localized antiapoptotic protein. J Virol 77: 11633–11643.

21. MalarkannanS, HorngT, ShihPP, SchwabS, ShastriN (1999) Presentation of out-of-frame peptide/MHC class I complexes by a novel translation initiation mechanism. Immunity 10: 681–690.

22. AndoniouCE, AndrewsDM, ManzurM, Ricciardi-CastagnoliP, Degli-EspostiMA (2004) A novel checkpoint in the Bcl-2-regulated apoptotic pathway revealed by murine cytomegalovirus infection of dendritic cells. J Cell Biol 166: 827–837.

23. BruneW, MenardC, HeesemannJ, KoszinowskiUH (2001) A ribonucleotide reductase homolog of cytomegalovirus and endothelial cell tropism. Science 291: 303–305.

24. ScalzoAA, FitzgeraldNA, WallaceCR, GibbonsAE, SmartYC, et al. (1992) The effect of the Cmv1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells. J Immunol 149: 581–589.

25. StoddartCA, CardinRD, BonameJM, ManningWC, AbenesGB, et al. (1994) Peripheral blood mononuclear phagocytes mediate dissemination of murine cytomegalovirus. J Virol 68: 6243–6253.

26. SaederupN, LinYC, DairaghiDJ, SchallTJ, MocarskiES (1999) Cytomegalovirus-encoded beta chemokine promotes monocyte-associated viremia in the host. Proc Natl Acad Sci U S A 96: 10881–10886.

27. SaederupN, AguirreSA, SparerTE, BouleyDM, MocarskiES (2001) Murine cytomegalovirus CC chemokine homolog MCK-2 (m131-129) is a determinant of dissemination that increases inflammation at initial sites of infection. Journal of Virology 75: 9966–9976.

28. BenedictCA, De TrezC, SchneiderK, HaS, PattersonG, et al. (2006) Specific remodeling of splenic architecture by cytomegalovirus. PLoS Pathog 2: e16.

29. AndrewsDM, AndoniouCE, GranucciF, Ricciardi-CastagnoliP, Degli-EspostiMA (2001) Infection of dendritic cells by murine cytomegalovirus induces functional paralysis. Nat Immunol 2: 1077–1084.

30. SacherT, PodlechJ, MohrCA, JordanS, RuzsicsZ, et al. (2008) The major virus-producing cell type during murine cytomegalovirus infection, the hepatocyte, is not the source of virus dissemination in the host. Cell Host & Microbe 3: 263–272.

31. ReddehaseMJ, WeilandF, MunchK, JonjicS, LuskeA, et al. (1985) Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs. J Virol 55: 264–273.

32. KarbowskiM, NorrisKL, ClelandMM, JeongSY, YouleRJ (2006) Role of Bax and Bak in mitochondrial morphogenesis. Nature 443: 658–662.

33. HengelH, ReuschU, GutermannA, ZieglerH, JonjicS, et al. (1999) Cytomegaloviral control of MHC class I function in the mouse. Immunol Rev 168: 167–176.

34. HeiseMT, ConnickM, VirginHW (1998) Murine cytomegalovirus inhibits interferon-gamma-induced antigen presentation to CD4 T cells by macrophages via regulation of expression of major histocompatibility complex class Ii associated genes. J Exp Med 187: 1037–1046.

35. RedpathS, AnguloA, GascoigneNRJ, GhazalP (1999) Murine cytomegalovirus infection down-regulates MHC class II expression on macrophages by induction of IL-10. J Immunol 162: 6701–6707.

36. WillisSN, ChenL, DewsonG, WeiA, NaikE, et al. (2005) Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 19: 1294–1305.

37. WarmingS, CostantinoN, CourtDL, JenkinsNA, CopelandNG (2005) Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res 33: e36.

38. RedwoodAJ, MesserleM, HarveyNL, HardyCM, KoszinowskiUH, et al. (2005) Use of a murine cytomegalovirus K181-derived bacterial artificial chromosome as a vaccine vector for immunocontraception. J Virol 79: 2998–3008.

39. JosefssonEC, JamesC, HenleyKJ, DebrincatMA, RogersKL, et al. (2011) Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets. J Exp Med 208: 2017–2031.

40. AllanJE, ShellamGR (1984) Genetic control of murine cytomegalovirus infection: virus titres in resistant and susceptible strains of mice. Arch Virol 81: 139–150.