Journal
CELL METABOLISM
Volume 16, Issue 2, Pages 265-273Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2012.07.005
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Funding
- NIH [DK067493, DK016746, P60 DK020579, RR024992, UL1 TR000448, HL057346, HL052172, DK042394, DK088227, DK93074, DK080339]
- JDRF [11-2011-40]
- Grants-in-Aid for Scientific Research [24659429] Funding Source: KAKEN
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Recent clinical and experimental evidence suggests that endoplasmic reticulum (ER) stress contributes to the life-and-death decisions of beta 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 beta 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-1 beta mRNA transcription, activates IL-1 beta production by the NLRP3 inflammasome, and mediates ER stress-mediated beta 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.
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