Open AccessThioredoxin‐interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress
Author(s) -
Lee Samuel,
Min Kim Soo,
Dotimas James,
Li Letitia,
Feener Edward P,
Baldus Stephan,
Myers Ronald B,
Chutkow William A,
Patwari Parth,
Yoshioka Jun,
Lee Richard T
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201302561
Subject(s) - txnip , unfolded protein response , protein disulfide isomerase , endoplasmic reticulum , endoplasmic reticulum associated protein degradation , microbiology and biotechnology , protein folding , calnexin , foldase , chemistry , biology , thioredoxin , calreticulin , biochemistry , enzyme , gene , escherichia coli , groel
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 ( PDI s). 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 PDI s 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.