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Exposure to the viral by-product dsRNA or Coxsackievirus B5 triggers pancreatic beta cell apoptosis via a Bim / Mcl-1 imbalance.
- Source :
-
PLoS pathogens [PLoS Pathog] 2011 Sep; Vol. 7 (9), pp. e1002267. Date of Electronic Publication: 2011 Sep 22. - Publication Year :
- 2011
-
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.
- Subjects :
- Animals
Bcl-2-Like Protein 11
Cell Line
Cell Survival
Coxsackievirus Infections pathology
Diabetes Mellitus, Type 1 etiology
Diabetes Mellitus, Type 1 metabolism
Diabetes Mellitus, Type 1 pathology
Diabetes Mellitus, Type 1 virology
Eukaryotic Initiation Factor-2 metabolism
Humans
Insulin-Secreting Cells pathology
Insulin-Secreting Cells virology
Male
Mitochondria metabolism
Myeloid Cell Leukemia Sequence 1 Protein
Phosphorylation
Rats
Rats, Wistar
Apoptosis
Apoptosis Regulatory Proteins metabolism
Coxsackievirus Infections metabolism
Enterovirus B, Human metabolism
Insulin-Secreting Cells metabolism
Membrane Proteins metabolism
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
RNA, Double-Stranded metabolism
RNA, Viral metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 7
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 21977009
- Full Text :
- https://doi.org/10.1371/journal.ppat.1002267