title: Immunoproteasome Activation During Early Antiviral Response in Mouse Pancreatic β-cells: New Insights into Auto-antigen Generation in Type I Diabetes?
abstract: Type 1 diabetes results from autoimmune destruction of the insulin producing pancreatic β-cells. The immunoproteasome, a version of the proteasome that collaborates with the 11S/PA28 activator to generate immunogenic peptides for presentation by MHC class I molecules, has long been implicated in the onset of the disease, but little is known about immunoproteasome function and regulation in pancreatic β-cells. Interesting insight into these issues comes from a recent analysis of the immunoproteasome expressed in pancreatic β-cells during early antiviral defenses mediated by interferon β (IFNβ), a type I IFN implicated in the induction of the diabetic state in human and animal models. Using mouse islets and the MIN6 insulinoma cell line, Freudenburg et al. found that IFNβ stimulates expression of the immunoproteasome and the 11S/PA28 activator in a manner fundamentally similar to the classic immuno-inducer IFNγ, with similar timing of mRNA accumulation and decline; similar transcriptional activation mediated primarily by the IRF1 and similar mRNA and protein levels. Furthermore, neither IFNβ nor IFNγ altered the expression of regular proteolytic subunits or prevented their incorporation into proteolytic cores. As a result, immunoproteasomes had stochastic combinations of immune and regular proteolytic sites, an arrangement that would likely increase the probability with which unique immunogenic peptides are produced. However, immunoproteasomes were activated by the 11S/PA28 only under conditions of ATP depletion. A mechanism that prevents the activation of immunoproteasome at high ATP levels has not been reported before and could have a major regulatory significance, as it could suppress the generation of immunogenic peptides as cell accumulate immunoproteasome and 11S/PA28, and activate antigen processing only when ATP levels drop. We discuss implications of these new findings on the link between early antiviral response and the onset of type 1 diabetes.
authors: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America ; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America ; Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Wieke
authors: W
authors: Freudenburg
authors: Madhav
authors: M
authors: Gautam
authors: Pradipta
authors: P
authors: Chakraborty
authors: Jared
authors: J
authors: James
authors: Jennifer
authors: J
authors: Richards
authors: Alison S
authors: AS
authors: Salvatori
authors: Aaron
authors: A
authors: Baldwin
authors: Jill
authors: J
authors: Schriewer
authors: R Mark L
authors: RM
authors: Buller
authors: John A
authors: JA
authors: Corbett
authors: Dorota
authors: D
authors: Skowyra
keywords: Autoantigen; IFNβ; IFNγ; Immunoproteasome; MIN6 cells; Mouse islets; Pancreatic β-cells; Type 1 diabetes
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