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Type I interferons mediate pancreatic toxicities of PERK inhibition

Qiujing Yu1, Bin Zhao1, Jun Gui1

  • 1Department of Animal Biology, School of Veterinary Medicine, Philadelphia, PA 19104;

Proceedings of the National Academy of Sciences of the United States of America
|December 3, 2015
PubMed

Insights

Pancreatic endoplasmic reticulum kinase (PERK) inhibition shows promise but causes pancreatic injury. Blocking the type 1 interferon (IFN) pathway prevents this toxicity, offering a therapeutic strategy for PERK-related disorders.

Area of Science:

  • Molecular Biology
  • Cellular Stress Response
  • Endocrinology

Background:

  • Pancreatic endoplasmic reticulum kinase (PERK) is crucial for the unfolded protein response (UPR).
  • PERK inhibitors show preclinical promise for neurodegenerative disorders and cancers.
  • PERK deficiency in mice and humans causes pancreatic injury and diabetes (e.g., Wolcott-Rallison syndrome).

Purpose of the Study:

  • To investigate the mechanism underlying PERK deficiency-induced pancreatic toxicity.
  • To determine the role of type 1 interferon (IFN) signaling in PERK-related pancreatic damage.
  • To evaluate the therapeutic potential of targeting IFNAR1 to mitigate PERK inhibitor toxicity.

Main Methods:

  • Generated whole-body and pancreas-specific Perk knockout mice.
  • Utilized bone marrow transplantation and cultured pancreatic islets.
  • Assessed IFNAR1 protein levels, IFN signaling, pancreatic tissue integrity, and diabetes development.

Main Results:

  • Perk ablation in mice increased IFNAR1 protein levels and IFN signaling in pancreatic tissues.
  • Concurrent IFNAR1 deletion attenuated pancreatic tissue loss and prevented diabetes in Perk-deficient mice.
  • Neutralizing IFNAR1 protected against pancreatic toxicity induced by PERK inhibitors.

Conclusions:

  • Stabilization of IFNAR1 and subsequent increased IFN signaling are major drivers of pancreatic injury in PERK-deficient states.
  • Targeting the IFN pathway, specifically IFNAR1, can mitigate pancreatic toxicity associated with PERK loss or inhibition.
  • Blocking IFNAR1 offers a potential therapeutic strategy for genetic disorders linked to PERK deficiency and for enhancing clinical use of PERK inhibitors.
Keywords:
PERKWolcott-Rallison syndromediabetesinterferonpancreas

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