A dynamic redox switch turns TRC40 into a chaperone protecting human cells against ATP-depleting, oxidative stress
Oxidative stress represents a major challenge for cellular proteostasis. The accumulation of reactive oxygen species, such as hydrogen peroxide, impairs the fidelity of protein biosynthesis and causes non-specific oxidative protein modifications and aggregation. This situation is further aggravated by the oxidative stress-mediated drop in cellular ATP levels, which reduces the activity of ATP-dependent chaperones and proteases. We now demonstrate that to cope with oxidative unfolding stress, human cells rely on the moonlighting function of TRC40, which turns from an ATP-dependent targeting factor into an ATP-independent chaperone upon oxidation. Controlled by a highly conserved redox switch, oxidized TRC40 forms chaperone-active tetramers and high-molecular complexes which prevent the aggregation of unfolding proteins. Acute oxidative stress leads to the reversible formation of distinct TRC40 foci, associated with the canonical chaperones Hsp70 and Hsp110, suggesting a role of these stress-induced structures in recovering and sorting aberrant proteins. Consistently, we discovered that TRC40 is essential upon ATP-depleting, oxidative stress conditions to counteract the accumulation of mis- and unfolded proteins, which are rapidly cleared in an TRC40-dependent manner. Our data reveal that TRC40 is an integral part of protein quality control and support its role as a triaging factor in cellular proteostasis.