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

Christine M. Oslowski, Takashi Hara, Bryan O'Sullivan-Murphy, Kohsuke Kanekura, Simin Lu, Mariko Hara, Shinsuke Ishigaki, Lihua J. Zhu, Emiko Hayashi, Simon T. Hui, Dale Greiner, Randal J. Kaufman, Rita Bortell, Fumihiko Urano

Research output: Contribution to journalArticlepeer-review

447 Scopus citations

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.

Original languageEnglish
Pages (from-to)265-273
Number of pages9
JournalCell metabolism
Volume16
Issue number2
DOIs
StatePublished - Aug 8 2012

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