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

PLoS Pathogens

Merja Roivainen¹  Esteban N. Gurzov²  Tatiane C. Nogueira²  Maikel L. Colli²  Alessandra K. Cardozo²  Decio L. Eizirik²  Florent Allagnat²  Daniel A. Cunha²  Anne Op de beeck³ 

[1] Intestinal Viruses Unit, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare (THL), Helsinki, Finland;Laboratory of Experimental Medicine, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium;Virology Unit, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium

关键词: Apoptosis;    Small interfering RNAs;    Mitochondria;    Protein expression;    Diabetes mellitus;    Phosphorylation;    Densitometry;    Coxsackieviruses;   

DOI  :  10.1371/journal.ppat.1002267

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY