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

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.

Targeting endoplasmic reticulum stress in insulin resistance

“…Consequently, a complex signaling cascade, involving IRE-1, ATF6, and PERK, is activated [5]. There are other proposed UPR sensors and mechanisms besides BiP, such as IRE-1b itself [82], which may directly interact through its luminal domain with unfolded proteins rather than BiP; the glycosylation status of ATF6 [83], which is greatly compromised during ER stress; or thioredoxin-interacting protein (TXNIP) [19], which regulates ER stress through protein disulfide isomerase (PDI) activation.…”

“…protein disulfide isomerase (PDI) activation. Interestingly, changes in PDI activity are associated with protein misfolding and ER stress, and TXNIP is one of the most strongly induced proteins in diabetic patients [19].…”

Mass spectrometry analysis of the oxidation states of the pro-oncogenic protein anterior gradient-2 reveals covalent dimerization via an intermolecular disulphide bond

“…A relatively high prooxidizing environment in the endoplasmic reticulum is thought to facilitate the iterative cycles of enzymatic cysteine reduction and oxidation on cysteine-rich client receptors destined for the secretory system and transmembrane destinations [27]. Classic thioredoxins have a conserved thioredoxin fold comprised of the CxxC motif that mediates covalent bond formation with cysteine containing client proteins followed by resolution through cycles of reduction-oxidation [28]. AGR2 by contrast is part of the thioredoxin superfamily that contain CxxS motifs and which lack the ability to exploit a two cysteine redox system that classically mediates client protein oxidation and reduction cycles [29].…”

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

“…In the liver, PPARA ameliorates inflammation by reducing ER stress in hepatocytes (Zhang et al, 2016). TXNIP is known to facilitate ER stress-induced NLRP3 inflammasome activation (Anthony and Wek, 2012;Lee et al, 2014b;Lerner et al, 2012;Oslowski et al, 2012). By regulating TXNIP levels, Gm15441 could serve as a link between PPARA and the NLRP3 inflammasome.…”