It has become increasingly apparent that reactive oxygen species (ROS) act as redox signals that influence development, growth, and aging. For example, low-level production of ROS by mitochondria is thought to activate mechanisms that increase lifespan. Our understanding of the mechanisms and scope of redox signaling is still limited, however. The transmembrane protein IRE-1 senses unfolded proteins within the endoplasmic reticulum (ER), and is critical for ER homeostasis and longevity assurance. IRE-1 activates the core unfolded protein response (UPR) through (1) oligomerization, (2) autophosphorylation, and (3) splicing the mRNA for the XBP-1 transcription factor. We found in C. elegans that ire-1 is needed for the SKN-1/Nrf-induced oxidative stress response (PLoS Gen 2013;9:e1003701), but the basis for this has remained unknown.
We have now determined in C. elegans that IRE-1 acts as a redox sensor that initiates p38 signaling, and SKN-1 activation. In response to oxidizing conditions in vivo, a conserved Cys within the kinase activation loop of IRE-1 rapidly becomes sulfenylated, a modification in which the –SH within Cys is oxidized to –SOH (sulfenic acid). While sulfenylation at this site inhibits the IRE-1 kinase and blocks the UPR, UPR activation inhibits IRE-1 sulfenylation, making these IRE-1 states mutually exclusive. Sulfenylated IRE-1 recruits the p38 MAPKKK (NSY-1), which then becomes activated by sulfenylation at a different position. This initiates p38 signaling and activates SKN-1. IRE-1 redox signaling can be triggered by global cytoplasmic ROS, or ROS that are produced locally by specific oxidases that are activated in response to xenobiotic or genetic stimuli. Like mitochondrially-derived ROS, these enzymatically-generated ROS stimulate longevity assurance mechanisms. This evolutionarily conserved pathway similarly controls the mammalian Nrf2(SKN-1)-mediated oxidative stress response.
Our findings define an unexpected mechanism of IRE-1 function, in which it acts as a redox-sensing switch that discriminates the ER and oxidative stress responses. This redox control of IRE-1 and p38 signaling may represent a broadly applicable paradigm for redox regulation of kinase activity. The data also reveal a model by which localized oxidase activation transduces and amplifies cellular stress signals, and thereby maintains homeostasis by initiating downstream protective responses that may promote longevity. .
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