학술논문
Glutaredoxin attenuates glutathione levels via deglutathionylation of Otub1 and subsequent destabilization of system x C
Document Type
Academic Journal
Author
Aboushousha R; Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, VT 05405, USA.; van der Velden J; Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, VT 05405, USA.; Hamilton N; Department of Chemistry, University of Vermont, Burlington, VT 05405, USA.; Peng Z; Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, VT 05405, USA.; MacPherson M; Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, VT 05405, USA.; Erickson C; Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, VT 05405, USA.; White S; Department of Neurological Sciences, University of Vermont, Burlington, VT 05405, USA.; Wouters EFM; Department of Respiratory Medicine, NUTRIM School of nutrition and translational research in metabolism, Maastricht University Medical Center, Maastricht, Netherlands.; Ludwig Boltzmann Institute for Lung Research, Vienna, Austria.; Reynaert NL; Department of Respiratory Medicine, NUTRIM School of nutrition and translational research in metabolism, Maastricht University Medical Center, Maastricht, Netherlands.; Seward DJ; Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, VT 05405, USA.; Li J; Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, VT 05405, USA.; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.; Janssen-Heininger YMW; Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, VT 05405, USA.
Source
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE
Subject
Language
English
Abstract
Glutathione (GSH) is a critical component of the cellular redox system that combats oxidative stress. The glutamate-cystine antiporter, system x C - , is a key player in GSH synthesis that allows for the uptake of cystine, the rate-limiting building block of GSH. It is unclear whether GSH or GSH-dependent protein oxidation [protein S -glutathionylation (PSSG)] regulates the activity of system x C - . We demonstrate that an environment of enhanced PSSG promotes GSH increases via a system x C - -dependent mechanism. Absence of the deglutathionylase, glutaredoxin (GLRX), augmented SLC7A11 protein and led to significant increases of GSH content. S -glutathionylation of C23 or C204 of the deubiquitinase OTUB1 promoted interaction with the E2-conjugating enzyme UBCH5A, leading to diminished ubiquitination and proteasomal degradation of SLC7A11 and augmentation of GSH, effects that were reversed by GLRX. These findings demonstrate an intricate link between GLRX and GSH via S -glutathionylation of OTUB1 and system x C - and illuminate a previously unknown feed-forward regulatory mechanism whereby enhanced GSH protein oxidation augments cellular GSH.