Beschreibung:
<jats:title>Significance</jats:title>
<jats:p>Inactivating pancreatic endoplasmic reticulum kinase (PERK) mutations cause pancreatic degeneration and diabetes in patients with Wolcott-Rallison syndrome. Pancreatic injury is also observed in mice upon PERK genetic ablation or treatment with PERK inhibitors. This toxicity (the mechanisms of which are poorly understood) impedes the clinical development of PERK inhibitors, which show promise against cancers and neurodegenerative diseases. Here we demonstrate that activation of type 1 interferon signaling occurs upon PERK ablation and is responsible for pancreatic injury and the loss of exocrine and endocrine tissues and functions. Neutralization of interferon signaling protects the pancreas from deleterious effects of PERK inhibitors. Temporally targeting the interferon pathway may help with the treatment of patients with Wolcott-Rallison syndrome and the use of PERK inhibitors against other diseases.</jats:p>