Redox controls UPR to control redox

Abstract

In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca 2+ efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

“…AIs block estrogen biosynthesis and induce EnR stress. Although the mechanisms are not well understood, EnR calcium levels drop during EnR stress (50). If EnR calcium levels drop too low, it will trigger extensive EnR stress, leading to cell death.…”

Peri/Epicellular Protein Disulfide Isomerase Sustains Vascular Lumen Caliber Through an Anticonstrictive Remodeling Effect

“…12,14 In particular, signaling of the unfolded protein response because of ER stress involves upstream and downstream oxidant or reductive processes, which can mediate both proadaptive or proapoptotic responses. 12,15 Overt disruption of redox homeostasis, however, leads to cell death during the unfolded protein response. 15 In addition to the ER pool, there is substantial evidence for an extracellular PDI pool 12,13 that is actually composed by cell surface-attached PDI (epicellular) plus secreted PDI (pericellular).…”

“…12,15 Overt disruption of redox homeostasis, however, leads to cell death during the unfolded protein response. 15 In addition to the ER pool, there is substantial evidence for an extracellular PDI pool 12,13 that is actually composed by cell surface-attached PDI (epicellular) plus secreted PDI (pericellular). As periand epicellular PDI are often indistinguishable, we coined the term peri/epicellular (pec) PDI to designate the extracellular pool.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…It is also a critical site of lipid and glucose metabolism, calcium homeostasis, and detoxification of drugs and metabolic byproducts. A biochemical process that is crucial for ER protein homeostasis is the formation of disulfide bridges, which is referred to as oxidative protein folding (Eletto et al, 2014). Disulfide bond generation by ER-localized protein FIGURE 3 | Receptor-mediated mitophagy.…”

“…disulfide isomerases is an oxidative process, and molecular O 2 and H 2 O 2 are the principal electron acceptors for oxidative folding in the ER (Eletto et al, 2014). Protein disulfide isomerases catalyze oxidation by coupling de novo disulfide formation to the reduction of O 2 to H 2 O 2.…”