Abstract
Protein homeostasis is an essential component of proper cellular function; however, sustaining protein health is a challenging task, especially during the aerobic lifestyle. Natural cellular oxidants may be involved in cell signaling and antibacterial defense; however, imbalanced levels can lead to protein misfolding, cell damage, and death. This merges together the processes of protein homeostasis and redox regulation. At the heart of this process are redox-regulated proteins or thiol-based switches, which carefully mediate various steps of protein homeostasis across folding, localization, quality control, and degradation pathways. In this review, we discuss the “redox code” of the proteostasis network, which shapes protein health during cell growth and aging. We describe the sources and types of thiol modifications and elaborate on diverse strategies of evolving antioxidant proteins in proteostasis networks during oxidative stress conditions. We also highlight the involvement of cysteines in protein degradation across varying levels, showcasing the importance of cysteine thiols in proteostasis at large. The individual examples and mechanisms raised open the door for extensive future research exploring the interplay between the redox and protein homeostasis systems. Understanding this interplay will enable us to re-write the redox code of cells and use it for biotechnological and therapeutic purposes.
Highlights
The stability of the cellular proteome is constantly challenged by conditions that cause proteotoxic stress, including errors during protein synthesis, undesirable protein modification, inherited polymorphisms, and native changes in physiological conditions, such as aging [1,2,3]
We have discussed the intersections between cysteine thiol switches, redox regulation, and protein homeostasis
Rather than viewing cysteines as homogenous in either reactivity, chemical mechanism, or “damaging” effect, we find that cysteine modifications appear in many configurations and form a rich tapestry of different molecular mechanisms
Summary
The stability of the cellular proteome is constantly challenged by conditions that cause proteotoxic stress, including errors during protein synthesis, undesirable protein modification (e.g., oxidation), inherited polymorphisms, and native changes in physiological conditions, such as aging [1,2,3] It is, not surprising that protein homeostasis (or proteostasis) is among the most important mechanisms maintaining the proper balance between protein biogenesis and its cellular function. To assist the ATP-dependent chaperones and their co-chaperones during stress conditions, other ATP-independent chaperones take on an essential role in maintaining a healthy proteome This is relevant under conditions associated with a drop in intracellular ATP reservoirs [45,46,47] (e.g., oxidative stress, mitochondrial dysfunction) or cellular locations depleted of ATP (e.g., bacterial periplasm). We will discuss the broad-scale relationship between cellular oxidation and proteostasis, focusing on the role of protein thiols as redox sensors and switches of the protein homeostasis network
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