The N-terminal cysteine is a dual sensor of oxygen and oxidative stress

Abstract

Significance Cellular homeostasis requires the sensing of and adaptation to dynamically changing levels of oxygen and reactive oxygen species (ROS). Here, we show that the Cys-branch of the Arg/N-degron pathway represents a cellular sensor for acute and chronic hypoxia, as well as oxidative stress. When the environment oscillates between normoxia and acute hypoxia, the enzymatic oxidation of the N-terminal cysteine (Nt-Cys) residues adjusts the levels of signaling molecules via the ubiquitin-proteasome system. However, if hypoxia becomes chronic, the Nt-Cys is chemically oxidized by consequent ROS to generate an N-degron that redirects the proteolytic flux of cognate substrates to the autophagy-lysosome system through reprograming of the ubiquitin code. These results provide critical insight into a first-line sensor and defense against oxidative stress.