Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome

Cell Metab. 2012 Aug 8;16(2):265-73. doi: 10.1016/j.cmet.2012.07.005.

Abstract

Recent clinical and experimental evidence suggests that endoplasmic reticulum (ER) stress contributes to the life-and-death decisions of β cells during the progression of type 1 and type 2 diabetes. Although crosstalk between inflammation and ER stress has been suggested to play a significant role in β cell dysfunction and death, a key molecule connecting ER stress to inflammation has not been identified. Here we report that thioredoxin-interacting protein (TXNIP) is a critical signaling node that links ER stress and inflammation. TXNIP is induced by ER stress through the PERK and IRE1 pathways, induces IL-1β mRNA transcription, activates IL-1β production by the NLRP3 inflammasome, and mediates ER stress-mediated β cell death. Collectively, our results suggest that TXNIP is a potential therapeutic target for diabetes and ER stress-related human diseases such as Wolfram syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Carrier Proteins / physiology
  • Cell Line
  • Chromatin Immunoprecipitation
  • Diabetes Mellitus / metabolism*
  • Endoplasmic Reticulum Stress / physiology*
  • Humans
  • Immunoblotting
  • Inflammasomes / metabolism*
  • Insulin-Secreting Cells / physiology*
  • Interleukin-1beta / metabolism
  • Luciferases
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / physiology*
  • Thioredoxins / genetics
  • Thioredoxins / metabolism*
  • Thioredoxins / physiology
  • eIF-2 Kinase / metabolism

Substances

  • Carrier Proteins
  • Inflammasomes
  • Interleukin-1beta
  • Membrane Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Txnip protein, mouse
  • Thioredoxins
  • Luciferases
  • Ern2 protein, mouse
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase