title: Type I interferons mediate pancreatic toxicities of PERK inhibition.
abstract: 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-specific Perk ablation 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 by Perk loss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated with PERK deficiency and help the clinical use of PERK inhibitors.
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Qiujing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Jun
authors.initials: J
authors.lastname: Gui
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Kanstantsin V
authors.initials: KV
authors.lastname: Katlinski
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Angela
authors.initials: A
authors.lastname: Brice
authors.affiliation: Department of Biochemistry, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: ChangHong
authors.initials: C
authors.lastname: Li
authors.affiliation: McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030;
authors.forename: Jake A
authors.initials: JA
authors.lastname: Kushner
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
authors.affiliation: Department of Biochemistry, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, Philadelphia, PA 19104; syfuchs@vet.upenn.edu.
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D007370:Interferon Type I / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000633:toxicity; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response; D015854:Up-Regulation / Q000187:drug effects; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D053148:Caspase 3; D007370:Interferon Type I; D047428:Protein Kinase Inhibitors; D053633:Receptor, Interferon alpha-beta; D019892:eIF-2 Kinase; C508032:Ifnar1 protein, mouse
keywords: PERK; Wolcott-Rallison syndrome; diabetes; interferon; pancreas