Thioredoxin-Interacting Protein Mediates ER Stress-Induced β Cell Death through Initiation of the Inflammasome

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 i...

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Bibliographic Details
Published in:Cell metabolism 2012-08, Vol.16 (2), p.265-273
Main Authors: Oslowski, Christine M., Hara, Takashi, O'Sullivan-Murphy, Bryan, Kanekura, Kohsuke, Lu, Simin, Hara, Mariko, Ishigaki, Shinsuke, Zhu, Lihua J., Hayashi, Emiko, Hui, Simon T., Greiner, Dale, Kaufman, Randal J., Bortell, Rita, Urano, Fumihiko
Format: Article
Language:English
Subjects:
Animals
Apoptosis - physiology
Carrier Proteins - genetics
Carrier Proteins - metabolism
Carrier Proteins - physiology
Cell Line
Chromatin Immunoprecipitation
Diabetes Mellitus - metabolism
eIF-2 Kinase - 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
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Summary: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. ► TXNIP is a critical signaling node that links ER stress and inflammation ► TXNIP is induced by ER stress through the PERK and IRE1 pathways ► TXNIP mediates ER stress-mediated β cell death
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2012.07.005