The balance between adaptive and apoptotic unfolded protein responses regulates β-cell death under ER stress conditions through XBP1, CHOP and JNK

Mol Cell Endocrinol. 2015 Sep 15;413:189-201. doi: 10.1016/j.mce.2015.06.025. Epub 2015 Jun 30.

Abstract

Endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR) have been implicated in β-cell death in type 1 and type 2 diabetes. However, the UPR is also a fundamental mechanism required for β-cell adaptation and survival. The mechanisms regulating the transition from adaptive to apoptotic UPR remain to be clarified. Here, we investigated the relationships between XBP1, CHOP and JNK in the transition from adaptive to apoptotic UPR and β-cell death in models of type 1 and type 2 diabetes. XBP1 inhibition potentiated cell death induced by pro-inflammatory cytokines or the saturated fatty acid palmitate in MIN6 β-cells. This response was prevented by CHOP inhibition. IRE1/XBP1 inhibition led to alterations in islets from diabetes-resistant ob/ob mice that resemble those found in diabetes, including increases in cell death and inflammation and antioxidant gene expression. Similarly, IRE1/XBP1 inhibition increased cell death in islets from NOD mice. On the other hand, JNK inhibition: 1) increased adaptive UPR and reduced cell death in islets from diabetic db/db mice, and 2) restored adaptive UPR while protecting against apoptotic UPR gene expression and β-cell death and dysfunction following cytokine exposure. These findings suggest that the balance between XBP1-mediated adaptive and CHOP-dependent apoptotic UPR is critically important for β-cell survival during ER stress. JNK activation regulates the transition from adaptive to apoptotic UPR, thus providing a mechanism for β-cell propensity to cell death rather than ER stress adaptation in type 1 and type 2 diabetes.

Keywords: Diabetes; Endoplasmic reticulum stress; Islets; Unfolded protein response; β-Cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum Stress*
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Regulatory Factor X Transcription Factors
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Unfolded Protein Response*
  • X-Box Binding Protein 1

Substances

  • DNA-Binding Proteins
  • Ddit3 protein, mouse
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Transcription Factor CHOP
  • MAP Kinase Kinase 4