Glutaredoxin attenuates glutathione levels via deglutathionylation of Otub1 and subsequent destabilization of system x_C.

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.

SUBMITTER: Aboushousha R 

PROVIDER: S-EPMC10499329 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature