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

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.

Expression of the enteroviral capsid protein VP1 in the islet cells of patients with type 1 diabetes is associated with induction of protein kinase R and downregulation of Mcl-1

“…As a result, Mcl-1 levels are expected to decline. This scenario has been confirmed recently in invitro studies where it was shown directly that treatment of cultured beta cells with the viral double stranded RNA (dsRNA) mimetic, polyinosinic:polycytidylic acid (poly-I:C; which will activate PKR) led to rapid loss of Mcl-1 from the cells [14].…”

“…Therefore, to maintain adequate levels of Mcl-1 within the cell, the protein must be synthesised and replenished at a rate that is at least equal to its rate of degradation. Under conditions in which PKR is activated, the translation initiation factor eIF2α becomes phosphorylated, leading to translational arrest and thereby to a reduction in the rate of Mcl-1 synthesis [14,28]. As a result, Mcl-1 levels are expected to decline.…”

“…PKR is an enzyme responsible for the activation of antiviral cascades within cells and is induced during enteroviral infection of cells [12,13]. Mcl-1 is an anti-apoptotic protein that is subject to rapid turnover in cells, such that it is degraded quickly during the translational arrest that ensues following viral infection [14]. Accordingly, we present a detailed analysis of the correlations between the immunodetection of VP1, induction of PKR and the level of Mcl-1 in individual beta cells in patients with type 1 diabetes.…”

Pancreatic Pathology in Type 1 Diabetes Mellitus

“…Therefore, we took advantage of this situation to study the expression of a labile, anti-apoptotic protein, Mcl-1, in VP1+ (PKR+) islet cells. Mcl-1 is constitutively expressed at high levels in most beta cells [60] and from in vitro studies, the protein is understood to be a critical determinant of beta cell fate in response to stressors (such as proinflammatory cytokines and viral infection) [65]. Importantly, we observed that Mcl-1 was selectively depleted from beta-cells expressing VP1 and PKR suggesting that these individual cells might then be rendered more sensitive to the detrimental effects of the pro-inflammatory mileu existing within inflamed islets [60].…”

Elicitation of T-cell responses by structural and non-structural proteins of coxsackievirus B4

“…Although common agents of acute infections, enteroviruses, and particularly coxsackievirus B types, may also be involved in the pathogenesis of type 1 diabetes (Craig et al, 2013). It has been suggested that enteroviruses either directly infect pancreatic islet b-cells leading to cell destruction (Colli et al, 2011;Ylipaasto et al, 2004) or trigger a T-cell immune response, which evokes proinflammatory mediators and the activation of the immune cells, which attack and destroy b-cells in pancreatic islets (Eizirik et al, 2009;Hämäläinen et al, 2014).…”