Homeostasis of the ER redox state subsequent to proteasome inhibition

Abstract

Endoplasmic reticulum (ER) maintains within, an oxidative redox state suitable for disulfide bond formation. We monitored the ER redox dynamics subsequent to proteasome inhibition using an ER redox probe ERroGFP S4. Proteasomal inhibition initially led to oxidation of the ER, but gradually the normal redox state was recovered that further led to a reductive state. These events were found to be concomitant with the increase in the both oxidized and reduced glutathione in the microsomal fraction, with a decrease of total intracellular glutathione. The ER reduction was suppressed by pretreatment of a glutathione synthesis inhibitor or by knockdown of ATF4, which induces glutathione-related genes. These results suggested cellular adaptation of ER redox homeostasis: (1) inhibition of proteasome led to accumulation of misfolded proteins and oxidative state in the ER, and (2) the oxidative ER was then reduced by ATF4 activation, followed by influx of glutathione into the ER.

Deciphering the Link Between ERUPR Signaling and MicroRNA in Pathogenesis of Alzheimer’s Disease

“…ER quality control helps in preserving proteostasis. ER-associated degradation (ERAD) is a process that helps in disposing of terminally misfolded proteins through ubiquitin–proteasome system ( Oku et al, 2021 ). When the misfolded proteins are overloaded the prototypical ER-stress sensors located at the ER membrane activate UPR.…”