Person: Yoshioka, Jun
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Yoshioka
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Jun
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Yoshioka, Jun
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Publication Thioredoxin-interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress(Blackwell Publishing Ltd, 2014) Lee, Samuel; Min Kim, Soo; Dotimas, James; Li, Tish; Feener, Edward Paul; Baldus, Stephan; Myers, Ronald B; Chutkow, William; Patwari, Parth; Yoshioka, Jun; Lee, RichardThe 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.Publication A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity(Nature Pub. Group, 2015) Qiao, Shuxi; Dennis, Michael; Song, Xiufeng; Vadysirisack, Douangsone D.; Salunke, Devika; Nash, Zachary; Yang, Zhifen; Liesa, Marc; Yoshioka, Jun; Matsuzawa, Shu-Ichi; Shirihai, Orian S.; Lee, Richard; Reed, John C.; Ellisen, LeifMacroautophagy (autophagy) is a critical cellular stress response; however, the signal transduction pathways controlling autophagy induction in response to stress are poorly understood. Here we reveal a new mechanism of autophagy control whose deregulation disrupts mitochondrial integrity and energy homeostasis in vivo. Stress conditions including hypoxia and exercise induce reactive oxygen species (ROS) through upregulation of a protein complex involving REDD1, an mTORC1 inhibitor and the pro-oxidant protein TXNIP. Decreased ROS in cells and tissues lacking either REDD1 or TXNIP increases catalytic activity of the redox-sensitive ATG4B cysteine endopeptidase, leading to enhanced LC3B delipidation and failed autophagy. Conversely, REDD1/TXNIP complex expression is sufficient to induce ROS, suppress ATG4B activity and activate autophagy. In Redd1−/− mice, deregulated ATG4B activity and disabled autophagic flux cause accumulation of defective mitochondria, leading to impaired oxidative phosphorylation, muscle ATP depletion and poor exercise capacity. Thus, ROS regulation through REDD1/TXNIP is physiological rheostat controlling stress-induced autophagy.Publication Diabetes regulates fructose absorption through thioredoxin-interacting protein(eLife Sciences Publications, Ltd, 2016) Dotimas, James R; Lee, Austin W; Schmider, Angela; Carroll, Shannon; Shah, Anu; Bilen, Julide; Elliott, Kayla R; Myers, Ronald B; Soberman, Roy; Yoshioka, Jun; Lee, RichardMetabolic studies suggest that the absorptive capacity of the small intestine for fructose is limited, though the molecular mechanisms controlling this process remain unknown. Here we demonstrate that thioredoxin-interacting protein (Txnip), which regulates glucose homeostasis in mammals, binds to fructose transporters and promotes fructose absorption by the small intestine. Deletion of Txnip in mice reduced fructose transport into the peripheral bloodstream and liver, as well as the severity of adverse metabolic outcomes resulting from long-term fructose consumption. We also demonstrate that fructose consumption induces expression of Txnip in the small intestine. Diabetic mice had increased expression of Txnip in the small intestine as well as enhanced fructose uptake and transport into the hepatic portal circulation. The deletion of Txnip in mice abolished the diabetes-induced increase in fructose absorption. Our results indicate that Txnip is a critical regulator of fructose metabolism and suggest that a diabetic state can promote fructose uptake. DOI: http://dx.doi.org/10.7554/eLife.18313.001Publication Thioredoxin Reductase 2 (Txnrd2) Regulates Mitochondrial Integrity in the Progression of Age-Related Heart Failure(John Wiley & Sons, Ltd, 2015) Yoshioka, Jun