#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Exposure to the Viral By-Product dsRNA or Coxsackievirus B5 Triggers Pancreatic Beta Cell Apoptosis via a Bim / Mcl-1 Imbalance


The rise in type 1 diabetes (T1D) incidence in recent decades is probably related to modifications in environmental factors. Viruses are among the putative environmental triggers of T1D. The mechanisms regulating beta cell responses to viruses, however, remain to be defined. We have presently clarified the signaling pathways leading to beta cell apoptosis following exposure to the viral mimetic double-stranded RNA (dsRNA) and a diabetogenic enterovirus (Coxsackievirus B5). Internal dsRNA induces cell death via the intrinsic mitochondrial pathway. In this process, activation of the dsRNA-dependent protein kinase (PKR) promotes eIF2α phosphorylation and protein synthesis inhibition, leading to downregulation of the antiapoptotic Bcl-2 protein myeloid cell leukemia sequence 1 (Mcl-1). Mcl-1 decrease results in the release of the BH3-only protein Bim, which activates the mitochondrial pathway of apoptosis. Indeed, Bim knockdown prevented both dsRNA- and Coxsackievirus B5-induced beta cell death, and counteracted the proapoptotic effects of Mcl-1 silencing. These observations indicate that the balance between Mcl-1 and Bim is a key factor regulating beta cell survival during diabetogenic viral infections.


Vyšlo v časopise: Exposure to the Viral By-Product dsRNA or Coxsackievirus B5 Triggers Pancreatic Beta Cell Apoptosis via a Bim / Mcl-1 Imbalance. PLoS Pathog 7(9): e32767. doi:10.1371/journal.ppat.1002267
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002267

Souhrn

The rise in type 1 diabetes (T1D) incidence in recent decades is probably related to modifications in environmental factors. Viruses are among the putative environmental triggers of T1D. The mechanisms regulating beta cell responses to viruses, however, remain to be defined. We have presently clarified the signaling pathways leading to beta cell apoptosis following exposure to the viral mimetic double-stranded RNA (dsRNA) and a diabetogenic enterovirus (Coxsackievirus B5). Internal dsRNA induces cell death via the intrinsic mitochondrial pathway. In this process, activation of the dsRNA-dependent protein kinase (PKR) promotes eIF2α phosphorylation and protein synthesis inhibition, leading to downregulation of the antiapoptotic Bcl-2 protein myeloid cell leukemia sequence 1 (Mcl-1). Mcl-1 decrease results in the release of the BH3-only protein Bim, which activates the mitochondrial pathway of apoptosis. Indeed, Bim knockdown prevented both dsRNA- and Coxsackievirus B5-induced beta cell death, and counteracted the proapoptotic effects of Mcl-1 silencing. These observations indicate that the balance between Mcl-1 and Bim is a key factor regulating beta cell survival during diabetogenic viral infections.


Zdroje

1. EizirikDLColliMLOrtisF 2009 The role of inflammation in insulitis and beta cell loss in type 1 diabetes. Nat Rev Endocrinol 5 219 226

2. TaoBPietropaoloMAtkinsonMSchatzDTaylorD 2010 Estimating the cost of type 1 diabetes in the U.S.: a propensity score matching method. PLoS One 5 e11501

3. ConcannonPRichSSNepomGT 2009 Genetics of type 1A diabetes. N Engl J Med 360 1646 1654

4. ColliMLMooreFGurzovENOrtisFEizirikDL 2010 MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta cell responses to the viral by-product double-stranded RNA. Hum Mol Genet 19 135 146

5. PattersonCCDahlquistGGGyurusEGreenASolteszG 2009 Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet 373 2027 2033

6. RoivainenMKlingelK 2010 Virus infections and type 1 diabetes risk. Curr Diab Rep 10 350 356

7. HyotyHHiltunenMKnipMLaakkonenMVahasaloP 1995 A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes 44 652 657

8. HorwitzMSBradleyLMHarbertsonJKrahlTLeeJ 1998 Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nat Med 4 781 785

9. ChehadehWWeillJVantyghemMCAlmGLefebvreJ 2000 Increased level of interferon-α in blood of patients with insulin-dependent diabetes mellitus: relationship with coxsackievirus B infection. J Infect Dis 181 1929 1939

10. DottaFCensiniSvan HalterenAGMarselliLMasiniM 2007 Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A 104 5115 5120

11. YoonJWAustinMOnoderaTNotkinsAL 1979 Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 300 1173 1179

12. RoivainenMRasilainenSYlipaastoPNissinenRUstinovJ 2000 Mechanisms of coxsackievirus-induced damage to human pancreatic beta cells. J Clin Endocrinol Metab 85 432 440

13. WagenknechtLERosemanJMHermanWH 1991 Increased incidence of insulin-dependent diabetes mellitus following an epidemic of Coxsackievirus B5. Am J Epidemiol 133 1024 1031

14. HoviTStenvikMRosenlewM 1996 Relative abundance of enterovirus serotypes in sewage differs from that in patients: clinical and epidemiological implications. Epidemiol Infect 116 91 97

15. HorwitzMSIlicAFineCBalasaBSarvetnickN 2004 Coxsackieviral-mediated diabetes: induction requires antigen-presenting cells and is accompanied by phagocytosis of beta cells. Clin Immunol 110 134 144

16. SchulteBMKramerMAnsemsMLankeKHvan DoremalenN 2010 Phagocytosis of enterovirus-infected pancreatic beta cells triggers innate immune responses in human dendritic cells. Diabetes 59 1182 1191

17. DevendraDJasinskiJMelanitouENakayamaMLiM 2005 Interferon-α as a mediator of polyinosinic:polycytidylic acid-induced type 1 diabetes. Diabetes 54 2549 2556

18. DogusanZGarciaMFlamezDAlexopoulouLGoldmanM 2008 Double-stranded RNA induces pancreatic beta cell apoptosis by activation of the TLR3 and IRF-3 pathways. Diabetes 57 1236 1245

19. RasilainenSYlipaastoPRoivainenMLapattoRHoviT 2004 Mechanisms of coxsackievirus B5 mediated beta cell death depend on the multiplicity of infection. J Med Virol 72 586 596

20. AllagnatFCunhaDMooreFVanderwindenJMEizirikDL 2011 Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to beta cell apoptosis. Cell Death Differ 18 328 337

21. GurzovENOrtisFCunhaDAGossetGLiM 2009 Signaling by IL-1β+IFN-γ and ER stress converge on DP5/Hrk activation: a novel mechanism for pancreatic beta-cell apoptosis. Cell Death Differ 11 1539 1550

22. CunhaDALadriereLOrtisFIgoillo-EsteveMGurzovEN 2009 Glucagon-like peptide-1 agonists protect pancreatic beta cells from lipotoxic endoplasmic reticulum stress through upregulation of BiP and JunB. Diabetes 58 2851 2862

23. GrunnetLGAikinRTonnesenMFParaskevasSBlaabjergL 2009 Proinflammatory cytokines activate the intrinsic apoptotic pathway in beta cells. Diabetes 58 1807 1815

24. GurzovENEizirikDL 2011 Bcl-2 proteins in diabetes: mitochondrial pathways of beta cell death and dysfunction. Trends Cell Biol 21 424 431

25. TaitSWGreenDR 2010 Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11 621 632

26. Yang-YenHF 2006 Mcl-1: a highly regulated cell death and survival controller. J Biomed Sci 13 201 204

27. CnopMHannaertJCHoorensAEizirikDLPipeleersDG 2001 Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. Diabetes 50 1771 1777

28. McKenzieMDJamiesonEJansenESScottCLHuangDC 2010 Glucose induces pancreatic islet cell apoptosis that requires the BH3-only proteins Bim and Puma and multi-BH domain protein Bax. Diabetes 59 644 652

29. ChenDWangMZhouSZhouQ 2002 HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim. EMBO J 21 6801 6810

30. KutukOLetaiA 2010 Displacement of Bim by Bmf and Puma rather than increase in Bim level mediates paclitaxel-induced apoptosis in breast cancer cells. Cell Death Differ 17 1624 1635

31. GurzovENGermanoCMCunhaDAOrtisFVanderwindenJM 2010 p53 up-regulated modulator of apoptosis (PUMA) activation contributes to pancreatic beta cell apoptosis induced by proinflammatory cytokines and endoplasmic reticulum stress. J Biol Chem 285 19910 19920

32. ChenLWillisSNWeiASmithBJFletcherJI 2005 Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17 393 403

33. RasschaertJLadriereLUrbainMDogusanZKatabuaB 2005 Toll-like receptor 3 and STAT-1 contribute to double-stranded RNA+ interferon-γ-induced apoptosis in primary pancreatic beta cells. J Biol Chem 280 33984 33991

34. CunhaDAHekermanPLadriereLBazarra-CastroAOrtisF 2008 Initiation and execution of lipotoxic ER stress in pancreatic beta cells. J Cell Sci 121 2308 2318

35. ThomasLWLamCEdwardsSW 2010 Mcl-1; the molecular regulation of protein function. FEBS Lett 584 2981 2989

36. EizirikDLCardozoAKCnopM 2008 The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29 42 61

37. GarciaMAGilJVentosoIGuerraSDomingoE 2006 Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev 70 1032 1060

38. EizirikDLMandrup-PoulsenT 2001 A choice of death-the signal-transduction of immune-mediated beta cell apoptosis. Diabetologia 44 2115 2133

39. LiWGaleyDMattsonMPNathA 2005 Molecular and cellular mechanisms of neuronal cell death in HIV dementia. Neurotox Res 8 119 134

40. DeBiasiRLKleinschmidt-DeMastersBKRichardson-BurnsSTylerKL 2002 Central nervous system apoptosis in human herpes simplex virus and cytomegalovirus encephalitis. J Infect Dis 186 1547 1557

41. AlterPJobmannMMeyerEPankuweitSMaischB 2001 Apoptosis in myocarditis and dilated cardiomyopathy: does enterovirus genome persistence protect from apoptosis? An endomyocardial biopsy study. Cardiovasc Pathol 10 229 234

42. Baca JonesCvon HerrathM 2011 Pathology and pathogenesis of virus infections. KaufmanSHERouseBTSacksDL The Immune Response to Infection First ed. Washington ASM Press 383 389

43. KiblerKVShorsTPerkinsKBZemanCCBanaszakMP 1997 Double-stranded RNA is a trigger for apoptosis in vaccinia virus-infected cells. J Virol 71 1992 2003

44. SmythDJCooperJDBaileyRFieldSBurrenO 2006 A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 38 617 619

45. AkiraSUematsuSTakeuchiO 2006 Pathogen recognition and innate immunity. Cell 124 783 801

46. GavathiotisESuzukiMDavisMLPitterKBirdGH 2008 BAX activation is initiated at a novel interaction site. Nature 455 1076 1081

47. Gomez-BougiePBatailleRAmiotM 2004 The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells. Eur J Immunol 34 3156 3164

48. HanJGoldsteinLAGastmanBRRabinovitzARabinowichH 2005 Disruption of Mcl-1.Bim complex in granzyme B-mediated mitochondrial apoptosis. J Biol Chem 280 16383 16392

49. BahlKHuebnerADavisRJWelshRM 2010 Analysis of apoptosis of memory T cells and dendritic cells during the early stages of viral infection or exposure to toll-like receptor agonists. J Virol 84 4866 4877

50. TaylorJMQuiltyDBanadygaLBarryM 2006 The vaccinia virus protein F1L interacts with Bim and inhibits activation of the pro-apoptotic protein Bax. J Biol Chem 281 39728 39739

51. ClarkePTylerKL 2009 Apoptosis in animal models of virus-induced disease. Nat Rev Microbiol 7 144 155

52. BeckhamJDGoodyRJClarkePBonnyCTylerKL 2007 Novel strategy for treatment of viral central nervous system infection by using a cell-permeating inhibitor of c-Jun N-terminal kinase. J Virol 81 6984 6992

53. SamuelMAMorreyJDDiamondMS 2007 Caspase 3-dependent cell death of neurons contributes to the pathogenesis of West Nile virus encephalitis. J Virol 81 2614 2623

54. AsfariMJanjicDMedaPLiGHalbanPA 1992 Establishment of 2-mercaptoethanol-dependent differentiated insulin-secreting cell lines. Endocrinology 130 167 178

55. PipeleersDGin't VeldPAVan de WinkelMMaesESchuitFC 1985 A new in vitro model for the study of pancreatic α and β cells. Endocrinology 117 806 816

56. MooreFNaamaneNColliMLBouckenoogheTOrtisF 2011 STAT1 is a master regulator of pancreatic beta cell apoptosis and islet inflammation. J Biol Chem 286 929 941

57. MooreFColliMLCnopMEsteveMICardozoAK 2009 PTPN2, a candidate gene for type 1 diabetes, modulates interferon-γ-induced pancreatic beta cell apoptosis. Diabetes 58 1283 1291

58. KatoHTakeuchiOMikamo-SatohEHiraiRKawaiT 2008 Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 205 1601 1610

59. KutluBCardozoAKDarvilleMIKruhofferMMagnussonN 2003 Discovery of gene networks regulating cytokine-induced dysfunction and apoptosis in insulin-producing INS-1 cells. Diabetes 52 2701 2719

60. HoorensAVan de CasteeleMKloppelGPipeleersD 1996 Glucose promotes survival of rat pancreatic beta cells by activating synthesis of proteins which suppress a constitutive apoptotic program. J Clin Invest 98 1568 1574

61. LiuDDarvilleMEizirikDL 2001 Double-stranded ribonucleic acid (RNA) induces beta cell Fas messenger RNA expression and increases cytokine-induced beta cell apoptosis. Endocrinology 142 2593 2599

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2011 Číslo 9
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#