Thioredoxin‐interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress

EMBO Molecular Medicine

Samuel Lee¹  Soo Min Kim¹  James Dotimas¹  Letitia Li¹  Edward P Feener²  Stephan Baldus³  Ronald B Myers¹  William A Chutkow⁴  Parth Patwari⁴  Jun Yoshioka⁴ 

[1] Harvard Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA, USA;The Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA;Department III of Internal Medicine, University Hospital of Cologne, Cologne, Germany;The Cardiovascular Division, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA, USA

关键词: endoplasmic reticulum stress;    protein disulfide isomerases;    thioredoxin‐interacting protein;    unfolded protein response;   

DOI  :  10.15252/emmm.201302561

来源: Wiley

【 摘 要 】

Abstract

The endoplasmic reticulum (ER) is responsible for protein folding, modification, and trafficking. Accumulation of unfolded or misfolded proteins represents the condition of ER stress and triggers the unfolded protein response (UPR), a key mechanism linking supply of excess nutrients to insulin resistance and type 2 diabetes in obesity. The ER harbors proteins that participate in protein folding including protein disulfide isomerases (PDIs). Changes in PDI activity are associated with protein misfolding and ER stress. Here, we show that thioredoxin-interacting protein (Txnip), a member of the arrestin protein superfamily and one of the most strongly induced proteins in diabetic patients, regulates PDI activity and UPR signaling. We found that Txnip binds to PDIs and increases their enzymatic activity. Genetic deletion of Txnip in cells and mice led to increased protein ubiquitination and splicing of the UPR regulated transcription factor X-box-binding protein 1 (Xbp1s) at baseline as well as under ER stress. Our results reveal Txnip as a novel direct regulator of PDI activity and a feedback mechanism of UPR signaling to decrease ER stress.

Synopsis

More and more evidence implicates ER stress in diabetes. Thioredoxin-interacting protein (Txnip) is here shown to interact with and regulate protein disulfide isomerases (PDIs) activity and ER stress. This study highlights new therapeutic targets for treating diabetes.

• An unbiased proteomics approach as well as specific pulldown assays revealed an interaction of thioredoxin-interacting protein (Txnip) with protein disulfide isomerases (PDIs).
• Txnip increases PDI activity, and Txnip knockout leads to increased protein ubiquitination and increased levels of Xbp1s, a marker of ER stress.
• Increased levels of Xbp1s in Txnip-KO mice is reversed by treatment with chemical chaperones.

【 授权许可】

CC BY   
© 2014 Brigham and Women's Hospital. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.