Thiol-Based Redox Signaling: Impacts on Molecular Chaperones and Cellular Proteostasis

Abstract

Signaling through protein cysteine residues to regulate diverse biological processes is widely conserved from bacterial to human cells. Differential cysteine reactivity enables cells to sense and respond to perturbations in the cellular redox environment, which may impact protein structure and activity. This chapter will focus on how redox signaling regulates components of the protein quality control network to mitigate proteotoxic stress caused by redox active compounds. While specifics of redox-based activation of the endoplasmic reticulum unfolded protein response and the cytoplasmic heat shock and oxidative stress responses differ, the presence of regulatory proteins containing reactive cysteines is a common feature. Moreover, several protein chaperones are reversibly regulated via cysteine switches that govern their ability to protect or refold damaged polypeptides. These responses are biologically indispensable, given the propensity of dysregulated cells to produce endogenous reactive oxygen species and the prevalence of thiol-reactive xenobiot-ics in the external environment.