Methionine sulfoxide reductase reverses oxidation of the nucleotide exchange factor Fes1 to regulate cytoplasmic Hsp70 chaperone cycle

Abstract

Methionine residues in proteins are targets of oxidation by reactive oxygen species (ROS). Selective oxidation of methionine to methionine sulfoxide (MetO) can allow for reversible, beneficial modification of proteins to limit cell damage during conditions of excess ROS. Methionine sulfoxide reductases (Msrs) are conserved enzymes that reduce MetO residues in proteins, serving to both limit the over‐oxidation of protein methionines, and to remove MetO adducts when stress subsides. Although loss of Msr function has been implicated in neurodegenerative disorders and aging, it is unclear how Msr activities influence these disease pathologies because the vast majority of their physiological substrates remain unknown.We have identified the cytoplasmic Hsp70 nucleotide exchange factor Fes1 as an Msr substrate in yeast. Under oxidative stress, Fes1 is oxidized at a cluster of N‐terminal methionine residues. Current data show that this Msr‐controlled modification reversibly regulates interaction between Fes1 and Hsp70, thereby modulating chaperone nucleotide exchange, ATP hydrolysis, and peptide binding and release. We suggest that these altered Hsp70 activities, as a consequence of Fes1 modification, may help cells cope with elevated ROS by limiting peptide aggregation and/or activating cellular stress response pathways, whereas sustained modification of Fes1 in the absence of Msr activity is detrimental to proteostasis under non‐stress conditions. Moreover, our studies with Fes1 uncovered that the two yeast Msr proteins (Mxr1 and Mxr2) are expressed in the cytoplasm, in contrast to prior studies of Mxr2 suggesting sole mitochondrial localization. We show that Mxr1 and Mxr2 co‐operate to regulate the redox state of Fes1 both in vivo and in vitro. Together, these studies provide a new perspective on how activities of the well‐studied Hsp70 family can be modulated by ROS, and further define how methionine modification is used as a means for cells to sense and respond to oxidative stress.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.