Universität zu Köln

Lee, Samuel, Kim, Soo Min, Dotimas, James ORCID: 0000-0002-6494-3265, Li, Letitia, Feener, Edward P., Baldus, Stephan, Myers, Ronald B., Chutkow, William A., Patwari, Parth, Yoshioka, Jun and Lee, Richard T. (2014). Thioredoxin-interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress. EMBO Mol. Med., 6 (6). S. 732 - 744. HOBOKEN: WILEY-BLACKWELL. ISSN 1757-4684

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lee, Samuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Soo Min UNSPECIFIED UNSPECIFIED UNSPECIFIED Dotimas, James UNSPECIFIED orcid.org/0000-0002-6494-3265 UNSPECIFIED Li, Letitia UNSPECIFIED UNSPECIFIED UNSPECIFIED Feener, Edward P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baldus, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Myers, Ronald B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chutkow, William A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Patwari, Parth UNSPECIFIED UNSPECIFIED UNSPECIFIED Yoshioka, Jun UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Richard T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-436770
DOI:	10.15252/emmm.201302561
Journal or Publication Title:	EMBO Mol. Med.
Volume:	6
Number:	6
Page Range:	S. 732 - 744
Date:	2014
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	1757-4684
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ER STRESS; GLUCOSE-HOMEOSTASIS; MOUSE MODEL; CELL-DEATH; ARRESTIN; TXNIP; LINKS; INFLAMMASOME; ADIPOGENESIS; EXPRESSION Multiple languages Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43677