Redox regulation of proteostasis

Oxidants produced through endogenous metabolism or encountered in the environment react directly with reactive sites in biological macromolecules. Many proteins, in particular, are susceptible to oxidative damage, which can lead to their altered structure and function. Such structural and functional changes trigger a cascade of events that influence key components of the proteostasis network. Here, we highlight recent advances in our understanding of how cells respond to the challenges of protein folding and metabolic alterations that occur during oxidative stress. Immediately after an oxidative insult, cells selectively block the translation of most new proteins and shift molecular chaperones from folding to a holding role to prevent wholesale protein aggregation. At the same time, adaptive responses in gene expression are induced, allowing for increased expression of antioxidant enzymes, enzymes that carry out the reduction of oxidized proteins, and molecular chaperones, all of which serve to mitigate oxidative damage and rebalance proteostasis. Likewise, concomitant activation of protein clearance mechanisms, namely proteasomal degradation and particular autophagic pathways, promotes the degradation of irreparably damaged proteins. As oxidative stress is associated with inflammation, aging, and numerous age-related disorders, the molecular events described herein are therefore major determinants of health and disease.