Thioredoxin-interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress.
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.
Harvard Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA The Cardiovascular Division, Department of Medicine, Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA Department III of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
Samuel
S
Lee
Harvard Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA The Cardiovascular Division, Department of Medicine, Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA.
Soo
S
Min Kim
Harvard Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA The Cardiovascular Division, Department of Medicine, Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA.
James
J
Dotimas
Harvard Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA The Cardiovascular Division, Department of Medicine, Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA.
Letitia
L
Li
The Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
Edward P
EP
Feener
Department III of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
Stephan
S
Baldus
Harvard Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA The Cardiovascular Division, Department of Medicine, Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA.
Ronald B
RB
Myers
The Cardiovascular Division, Department of Medicine, Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA.
William A
WA
Chutkow
The Cardiovascular Division, Department of Medicine, Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA.
Parth
P
Patwari
The Cardiovascular Division, Department of Medicine, Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA.
Jun
J
Yoshioka
Harvard Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA The Cardiovascular Division, Department of Medicine, Harvard Medical School Brigham and Women's Hospital, Cambridge, MA, USA RLee@partners.org.
Richard T
RT
Lee
D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D009154:Mutation; D019704:Protein Disulfide-Isomerases / Q000032:analysis / Q000378:metabolism*; D013879:Thioredoxins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D056811:Unfolded Protein Response
D002352:Carrier Proteins; C486715:TXNIP protein, human; C445672:Txnip protein, mouse; D013879:Thioredoxins; C496931:PDIA6 protein, human; C526507:Pdia6 protein, mouse; D019704:Protein Disulfide-Isomerases
endoplasmic reticulum stress; protein disulfide isomerases; thioredoxin‐interacting protein; unfolded protein response