Thioredoxin-interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress
| Autor: | Richard T. Lee, Soo Min Kim, James R Dotimas, Stephan Baldus, Samuel Lee, Letitia Li, Parth Patwari, William A. Chutkow, Edward P. Feener, Ronald B Myers, Jun Yoshioka |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Thioredoxin-Interacting Protein
Protein Disulfide-Isomerases Biology Endoplasmic Reticulum Cell Line 03 medical and health sciences Gene Knockout Techniques Mice 0302 clinical medicine Thioredoxins Animals Humans Protein disulfide-isomerase Transcription factor Research Articles 030304 developmental biology 0303 health sciences thioredoxin-interacting protein Endoplasmic reticulum Ubiquitination unfolded protein response Endoplasmic Reticulum Stress Protein ubiquitination Biochemistry Mutation Unfolded protein response protein disulfide isomerases Molecular Medicine Protein folding Carrier Proteins 030217 neurology & neurosurgery TXNIP Gene Deletion |
| Zdroj: | EMBO Molecular Medicine |
| ISSN: | 1757-4684 1757-4676 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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