Ubiquitin D regulates IRE1 α/c-Jun N-terminal kinase (JNK) protein-dependent apoptosis in pancreatic beta cells

Pro-inflammatory cytokines contribute to pancreatic beta cell apoptosis in type 1 diabetes at least in part by inducing endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). It remains to be determined what causes the transition from "physiological" to "apoptotic" UPR, but accumulating evidence indicates that signaling by the ER transmembrane protein IRE1 alpha is critical for this transition. IRE1 alpha activation is regulated by both intra-ER and cytosolic cues. We evaluated the role for the presently discovered cytokine-induced and IRE1 alpha-interacting protein ubiquitin D (UBD) on the regulation of IRE1 alpha and its downstream targets. UBD was identified by use of a MAPPIT (mammalian protein-protein interaction trap)-based IRE1 alpha interactome screen followed by comparison against functional genomic analysis of human and rodent beta cells exposed to pro-inflammatory cytokines. Knockdown ofUBDin human and rodent beta cells and detailed signal transduction studies indicated that UBD modulates cytokine-induced UPR/IRE1 alpha activation and apoptosis. UBD expression is induced by the pro-inflammatory cytokines interleukin (IL)-1 beta and interferon (IFN)-gamma in rat and human pancreatic beta cells, and it is also up-regulated in beta cells of inflamed islets from non-obese diabetic mice. UBD interacts with IRE1 alpha in human and rodent beta cells, modulating IRE1 alpha-dependent activation of JNK and cytokine-induced apoptosis. Our data suggest that UBD provides a negative feedback on cytokine-induced activation of the IRE1 alpha/JNK pro-apoptotic pathway in cytokine-exposed beta cells

On the immense variety and complexity of circumstances conditioning pancreatic beta-cell apoptosis in type 1 diabetes.

CommentJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: no.jinfo:eu-repo/semantics/publishe

Beta cell expression of enteroviral receptor CAR and islet inflammation in human type 1 diabetes

info:eu-repo/semantics/nonPublishe

Immunology in the clinic review series; focus on type 1 diabetes and viruses: how viral infections modulate beta cell function.

Type 1 diabetes mellitus (T1DM) is a multi-factorial immune-mediated disease characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically susceptible individuals. Epidemiological evidence has also documented the constant rise in the incidence of T1DM worldwide, with viral infections representing one of the candidate environmental risk factors identified by several independent studies. In fact, epidemiological data showed that T1DM incidence increases after epidemics due to enteroviruses and that enteroviral RNA can be detected in the blood of >50% of T1DM patients at the time of disease onset. Furthermore, both in-vitro and ex-vivo studies have shown that viruses can infect pancreatic beta cells with consequent effects ranging from functional damage to cell death.FLWINinfo:eu-repo/semantics/publishe

Dimostrazione dei linfociti T CD8 autoreattivi contro autoantigeni insulari nell’insulite dei pazienti con diabete tipo 1. SID 2012, 24th National Conference, Società Italiana Diabetologia

info:eu-repo/semantics/nonPublishe

Coxsackie-Virus and Insulitis: Diabetes and Virus

info:eu-repo/semantics/published

Increased expression of microRNA miR-326 in type 1 diabetic patients with ongoing islet autoimmunity.

The current paradigm that microRNAs represent a new layer of gene regulation has generated much interest in this field. MicroRNAs have emerged as important regulatory factors involved in the developmental processes and in the regulation of insulin secretion and signalling. Furthermore, recent studies revealed an altered microRNA profiling in lymphocytes of patients with autoimmune diseases like multiple sclerosis, in which a hyperexpression of miR-326 was reported. Here, we analysed the expression levels of miR-326 in peripheral blood lymphocytes from type 1 diabetic (T1D) patients in relationship with ongoing islet autoimmunity.FLWINinfo:eu-repo/semantics/publishe

Increased expression of microRNA miR-326 in type 1 diabetic patients with ongoing islet autoimmunity

info:eu-repo/semantics/nonPublishe

Beta cell expression of enteroviral receptor CAR and islets inflammation in human type 1 diabetes

info:eu-repo/semantics/nonPublishe

Viral infections and diabetes.

Type 1 diabetes mellitus (T1DM) is a multi-factorial autoimmune disease determined by the interaction of genetic, environmental and immunologic factors. One of the environmental risk factors identified by a series of independent studies is represented by viral infection, with strong evidence showing that viruses can indeed infect pancreatic beta cells with consequent effects ranging from functional damage to cell death. In this chapter we review the data obtained both in man and in experimental animal models in support of the potential participation of viral infections to Type 1 diabetes pathogenesis, with a particular emphasis on virus-triggered islet inflammation, beta-cell dysfunction and autoimmunity.info:eu-repo/semantics/publishe