Impairment of Immunoproteasome Function by β5i/LMP7 Subunit Deficiency Results in Severe Enterovirus Myocarditis

English version České info

Proteasomes recognize and degrade poly-ubiquitinylated proteins. In infectious disease, cells activated by interferons (IFNs) express three unique catalytic subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 forming an alternative proteasome isoform, the immunoproteasome (IP). The in vivo function of IPs in pathogen-induced inflammation is still a matter of controversy. IPs were mainly associated with MHC class I antigen processing. However, recent findings pointed to a more general function of IPs in response to cytokine stress. Here, we report on the role of IPs in acute coxsackievirus B3 (CVB3) myocarditis reflecting one of the most common viral disease entities among young people. Despite identical viral load in both control and IP-deficient mice, IP-deficiency was associated with severe acute heart muscle injury reflected by large foci of inflammatory lesions and severe myocardial tissue damage. Exacerbation of acute heart muscle injury in this host was ascribed to disequilibrium in protein homeostasis in viral heart disease as indicated by the detection of increased proteotoxic stress in cytokine-challenged cardiomyocytes and inflammatory cells from IP-deficient mice. In fact, due to IP-dependent removal of poly-ubiquitinylated protein aggregates in the injured myocardium IPs protected CVB3-challenged mice from oxidant-protein damage. Impaired NFκB activation in IP-deficient cardiomyocytes and inflammatory cells and proteotoxic stress in combination with severe inflammation in CVB3-challenged hearts from IP-deficient mice potentiated apoptotic cell death in this host, thus exacerbating acute tissue damage. Adoptive T cell transfer studies in IP-deficient mice are in agreement with data pointing towards an effective CD8 T cell immune. This study therefore demonstrates that IP formation primarily protects the target organ of CVB3 infection from excessive inflammatory tissue damage in a virus-induced proinflammatory cytokine milieu.

Vyšlo v časopise: Impairment of Immunoproteasome Function by β5i/LMP7 Subunit Deficiency Results in Severe Enterovirus Myocarditis. PLoS Pathog 7(9): e32767. doi:10.1371/journal.ppat.1002233
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002233

Souhrn

Zdroje

1. WatanabeYSuzukiOHaruyamaTAkaikeT 2003 Interferon-gamma induces reactive oxygen species and endoplasmic reticulum stress at the hepatic apoptosis. J Cell Biochem 89 244 253

2. SiXNMcManusBMZhangJCYuanJCheungC 2005 Pyrrolidine dithiocarbamate reduces coxsackievirus B3 replication through inhibition of the ubiquitin-proteasome pathway. J Virol 79 8014 8023

3. GoldbergAL 2003 Protein degradation and protection against misfolded or damaged proteins. Nature 426 895 899

4. HerrmannJSoaresSMLermanLOLermanA 2008 Potential role of the ubiquitin-proteasome system in atherosclerosis. J Am Coll Cardiol 51 2003 2010

5. PattersonCIkeCWillisPWStoufferGAWillisMS 2007 The bitter end: the ubiquitin-proteasome system and cardiac dysfunction. Circulation 115 1456 1463

6. WillisMSTownley-TilsonWHDKangEYHomeisterJWPattersonC 2010 Sent to Destroy The Ubiquitin Proteasome System Regulates Cell Signaling and Protein Quality Control in Cardiovascular Development and Disease. Circ Res 106 463 478

7. DantumaNPLindstenK 2010 Stressing the ubiquitin-proteasome system. Cardiovasc Res 85 263 271

8. SchwartzALCiechanoverA 1999 The ubiquitin-proteasome pathway and pathogenesis of human diseases. Annu Rev Med 50 57 74

9. YewdellJW 2005 The seven dirty little secrets of major histocompatibility complex class I antigen processing. Immunol Rev 207 8 18

10. PickartCM 2001 Mechanisms underlying ubiquitination. Annu Rev Biochem 70 503 533

11. KloetzelPM 2001 Antigen processing by the proteasome. Nat Rev Mol Cell Biol 2 179 187

12. LiuYCPenningerJKarinM 2005 Immunity by ubiquitylation: A reversible process of modification. Nat Rev Immunol 5 941 952

13. GrollMDitzelLLoweJStockDBochtlerM 1997 Structure of 20S proteasome from yeast at 2.4 angstrom resolution. Nature 386 463 471

14. AkiMShimbaraNTakashinaMAkiyamaKKagawaS 1994 Interferon-Gamma Induces Different Subunit Organizations and Functional Diversity of Proteasomes. J Biochem (Tokyo) 115 257 269

15. SijtsAJAMStanderaSToesREMRuppertTBeekmanNJCM 2000 MHC class I antigen processing of an Adenovirus CTL epitope is linked to the levels of immunoproteasomes in infected cells. J Immunol 164 4500 4506

16. SchwarzKvan den BroekMKostkaSKraftRSozaA 2000 Overexpression of the proteasome subunits LMP2, LMP7, and MECL-1, but not PA28 alpha/beta, enhances the presentation of an immunodominant lymphocytic choriomeningitis virus T cell epitope. J Immunol 165 768 778

17. StrehlBJoerisTRiegerMVisekrunaATextoris-TaubeK 2006 Immunoproteasomes are essential for clearance of Listeria monocytogenes in nonlymphoid tissues but not for induction of bacteria-specific CD8(+) T cells. J Immunol 177 6238 6244

18. ShinECSeifertUKatoTRiceCMFeinstoneSM 2006 Virus-induced type IIFN stimulates generation of immunoproteasomes at the site of infection. J Clin Invest 116 3006 3014

19. JakelSKuckelkornUSzalayGPlotzMTextoris-TaubeK 2009 Differential Interferon Responses Enhance Viral Epitope Generation by Myocardial Immunoproteasomes in Murine Enterovirus Myocarditis. Am J Pathol 175 510 518

20. DeolPZaissDMWMonacoJJSijtsAJAM 2007 Rates of processing determine the immunogenicity of immunoproteasome-generated epitopes. J Immunol 178 7557 7562

21. FehlingHJSwatWLaplaceCKuhnRRajewskyK 1994 Mhc Class-I Expression in Mice Lacking the Proteasome Subunit Lmp-7. Science 265 1234 1237

22. VankaerLAshtonrickardtPGEichelbergerMGaczynskaMNagashimaK 1994 Altered Peptidase and Viral-Specific T-Cell Response in Lmp2 Mutant Mice. Immunity 1 533 541

23. ChenWSNorburyCCChoYJYewdellJWBenninkJR 2001 Immunoproteasomes shape immunodominance hierarchies of antiviral CD8(+) T cells at the levels of T cell repertoire and presentation of viral antigens. J Exp Med 193 1319 1326

24. SeifertUBialyLPEbsteinFBech-OtschirDVoigtA 2010 Immunoproteasomes Preserve Protein Homeostasis upon Interferon-Induced Oxidative Stress. Cell 142 613 624

25. GomesAVZongCEdmondsonRDLiXStefaniE 2006 Mapping the murine cardiac 26S proteasome complexes. Circ Res 99 362 371

26. GriffinTANandiDCruzMFehlingHJVan KaerL 1998 Immunoproteasome assembly: Cooperative incorporation of interferon gamma (IFN-gamma)-inducible subunits. J Exp Med 187 97 104

27. KlingelKHohenadlCCanuAAlbrechtMSeemannM 1992 Ongoing Enterovirus-Induced Myocarditis Is Associated with Persistent Heart-Muscle Infection -⁠ Quantitative-Analysis of Virus-Replication, Tissue-Damage, and Inflammation. Proc Natl Acad Sci U S A 89 314 318

28. FeldmanAMMcNamaraD 2000 Myocarditis. N Engl J Med 343 1388 1398

29. KlingelKSchnorrJJSauterMSzalayGKandolfR 2003 beta 2-microglobulin-associated regulation of interferon-gamma and virus-specific immunoglobulin G confer resistance against the development of chronic coxsackievirus myocarditis. Am J Pathol 162 1709 1720

30. HensleySEZankerDDolanBPDavidAHickmanHD 2010 Unexpected Role for the Immunoproteasome Subunit LMP2 in Antiviral Humoral and Innate Immune Responses. J Immunol 184 4115 4122

31. OsterlohPLinkemannKTenzerSRammenseeHGRadsakMP 2006 Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses. Proc Natl Acad Sci U S A 103 5042 5047

32. HenkeAHuberSStelznerAWhittonJL 1995 The Role of Cd8(+) T-Lymphocytes in Coxsackievirus B3-Induced Myocarditis. J Virol 69 6720 6728

33. SchmidtNGonzalezEVisekrunaAKuhlAALoddenkemperC 2010 Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis. Gut 59 896 906

34. NussbaumAKRodriguez-CarrenoMPBenningNBottenJWhittonJL 2005 Immunoproteasome-deficient mice mount largely normal CD8(+) T cell responses to lymphocytic choriomeningitis virus infection and DNA vaccination. J Immunol 175 1153 1160

35. VoigtAJakelSTextoris-TaubeKKellerCDrungI 2010 Generation of in silico predicted coxsackievirus B3-derived MHC class I epitopes by proteasomes. Amino Acids 39 243 255

36. PonnappanSPonnappanU 2011 Aging and Immune Function: Molecular Mechanisms to Interventions. Antioxid Redox Signaling 14 1551 1585

37. BeckMAShiQMorrisVCLevanderOA 1995 Rapid Genomic Evolution of A Nonvirulent Coxsackievirus B3 in Selenium-Deficient Mice Results in Selection of Identical Virulent Isolates. Nat Med 1 433 436

38. BeckMAEsworthyRSHoYSChuFF 1998 Glutathione peroxidase knockout mice are susceptible to a normally avirulent strain of coxsackievirus B3. FASEB J 12 A43

39. BeckMAHandyJLevanderOA 2000 The role of oxidative stress in viral infections. Neuroimmunomodulation 917 906 912

40. RahnefeldAEbsteinFAlbrechtNOpitzEKuckelkornU 2011 Antigen Presentation Capacity of Dendritic Cells is Impaired in Ongoing Enterovirus-Myocarditis. Eur J Immunol. E-pub ahead of print doi:10.1002/eji.201041039

41. GruneTJungTMerkerKDaviesKJA 2004 Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and 'aggresomes' during oxidative stress, aging, and disease. Int J Biochem Cell Biol 36 2519 2530

42. PiccininiAMMidwoodKS 2010 DAMPening Inflammation by Modulating TLR Signalling. Mediators Inflamm. E-pub ahead of print pii:672395

43. CunninghamSGrahamCHutchinsonMDrooganAO'RourkeL 2005 Pharmacogenomics of responsiveness to interferon IFN-beta treatment in multiple sclerosis: A genetic screen of 100 type I interferon-inducible genes. Clin Pharmacol Ther 78 635 646

44. BaslerMDajeeMMollCGroettrupMKirkCJ 2010 Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome. J Immunol 185 634 641

45. AJoerisTSeidelDKroesenALoddenkemperC 2006 Proteasome-mediated degradation of I kappa B alpha and processing of p105 in Crohn disease and ulcerative colitis. J Clin Invest 116 3195 3203

46. WullaertABonnetMCPasparakisM 2011 NF-kappa B in the regulation of epithelial homeostasis and inflammation. Cell Res 21 146 158

47. MitsiadesNMitsiadesCSPoulakiVChauhanDRichardsonPG 2002 Biologic sequelae of nuclear factor-kappa B blockade in multiple myeloma: therapeutic applications. Blood 99 4079 4086

48. KandolfRHofschneiderPH 1985 Molecular-Cloning of the Genome of A Cardiotropic Coxsackie-B3 Virus -⁠ Full-Length Reverse-Transcribed Recombinant Cdna Generates Infectious Virus in Mammalian-Cells. Proc Natl Acad Sci U S A 82 4818 4822

49. NesvizhskiiAIKellerAKolkerEAebersoldR 2003 A statistical model for identifying proteins by tandem mass spectrometry. Anal Chem 75 4646 4658

50. SzalayGSauterMHaldJWeinzierlAKandolfR 2006 Sustained nitric oxide synthesis contributes to immunopathology in ongoing myocarditis attributable to interleukin-10 disorders. Am J Pathol 169 2085 2093