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Type I interferons mediate pancreatic toxicities of PERK inhibition
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Type I interferons mediate pancreatic toxicities of PERK inhibition
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Journal Article
Type I interferons mediate pancreatic toxicities of PERK inhibition
2015
Overview
The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specificPerkablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues. Concurrent IFNAR1 deletion attenuated the loss of PERK-deficient exocrine and endocrine pancreatic tissues and prevented the development of diabetes. Experiments using pancreas-specific Perk knockouts, bone marrow transplantation, and cultured pancreatic islets demonstrated that stabilization of IFNAR1 and the ensuing increased IFN signaling in pancreatic tissues represents a major driver of injury triggered byPerkloss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated withPERKdeficiency and help the clinical use of PERK inhibitors.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Diabetes
/ Diabetes Mellitus, Experimental - enzymology
/ Diabetes Mellitus, Experimental - pathology
/ Down-Regulation - drug effects
/ eIF-2 Kinase - antagonists & inhibitors
/ Endoplasmic Reticulum - drug effects
/ Endoplasmic Reticulum - metabolism
/ Enzyme Activation - drug effects
/ Fluorescent Antibody Technique
/ Interferon Type I - metabolism
/ Islets of Langerhans - drug effects
/ Islets of Langerhans - metabolism
/ Kinases
/ Mice
/ Protein Kinase Inhibitors - toxicity
/ Receptor, Interferon alpha-beta - metabolism
/ Signal Transduction - drug effects
/ Toxicity
