PMID:21977009

Citation	Colli, ML, Nogueira, TC, Allagnat, F, Cunha, DA, Gurzov, EN, Cardozo, AK, Roivainen, M, Op de Beeck, A and Eizirik, DL (2011) Exposure to the viral by-product dsRNA or Coxsackievirus B5 triggers pancreatic beta cell apoptosis via a Bim / Mcl-1 imbalance. PLoS Pathog. 7:e1002267
Abstract	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.
Links	PubMed PMC3178579 Online version:10.1371/journal.ppat.1002267
Keywords	Animals; Apoptosis; Apoptosis Regulatory Proteins/metabolism; Cell Line; Cell Survival; Coxsackievirus Infections/metabolism; Coxsackievirus Infections/pathology; Diabetes Mellitus, Type 1/etiology; Diabetes Mellitus, Type 1/metabolism; Diabetes Mellitus, Type 1/pathology; Diabetes Mellitus, Type 1/virology; Enterovirus B, Human/metabolism; Eukaryotic Initiation Factor-2/metabolism; Humans; Insulin-Secreting Cells/metabolism; Insulin-Secreting Cells/pathology; Insulin-Secreting Cells/virology; Male; Membrane Proteins/metabolism; Mitochondria/metabolism; Phosphorylation; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism; RNA, Double-Stranded/metabolism; RNA, Viral/metabolism; Rats; Rats, Wistar
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:MCL1		GO:0043066: negative regulation of apoptotic process	ECO:0000315:		P		Fig.2a Mcl-1 protein expression by gradually decreases after PIC transfection fig.2d Mcl-1 KO by siRNAs increase cleavage of caspase 3 and 9	complete CACAO 4591

References

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