Abstract
The endoplasmic reticulum (ER) has emerged as a source of hydrogen peroxide (H2O2) and a hub for peroxide-based signaling events. Here we outline cellular sources of ER-localized peroxide, including sources within and near the ER. Focusing on three ER-localized proteins—the molecular chaperone BiP, the transmembrane stress-sensor IRE1, and the calcium pump SERCA2—we discuss how post-translational modification of protein cysteines by H2O2 can alter ER activities. We review how changed activities for these three proteins upon oxidation can modulate signaling events, and also how cysteine oxidation can serve to limit the cellular damage that is most often associated with elevated peroxide levels.
Highlights
All cells are susceptible to oxidative damage
We focus on three targets of reversible modification by endoplasmic reticulum (ER) peroxide: the molecular chaperone BiP, the transmembrane stress-sensor IRE1, and the calcium pump SERCA2
Significant enzymatic sources for H2 O2 exist distributed throughout the cell, including plasma membrane NADPH oxidases (NOX) [82] and peroxisomal beta-oxidation [83], and intriguing connections have been made between these local sites of reactive oxygen species (ROS) generation and ER function
Summary
All cells are susceptible to oxidative damage. Damage often appears concomitant with a buildup of reactive oxidants and/or a loss of antioxidant systems. An accumulation of cellular reactive oxygen species (ROS) has attracted much attention as a source of cellular damage and a cause for a loss of cellular function [1] In keeping with these observations, most historical discussions of ROS focus on the need to defend against the toxic and unavoidable consequences of cellular ROS production, in order to limit cellular dysfunction and disease. An appreciation of the diversity of ROS, the benefits provided by the action of some ROS as signal molecules, and the variety of cellular ROS sources (beyond the mitochondria) have begun to permeate the literature (e.g., see [2,3,4]) These new views regarding ROS have begun to refocus the discussion of ROS production and utilization by cells. We discuss how reversible post-translational oxidation of cysteine residues in BiP, IRE1, or SERCA2 by peroxide alters protein function, and how altered activities for these proteins can help the ER adapt to rising peroxide levels
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