The Cys/N-degron pathway in the ubiquitin–proteasome system and autophagy

All 20 amino acids can serve as N-degrons, directly or through post-translational modifications, when exposed at the protein N termini, providing a means for degrading all cellular proteins. Nt-Arg is a common element in the N-degrons generated from post-translational modifications of Cys as well as Asn, Gln, Asp, and Glu at the N termini. The resulting N-degrons are differentially recognized by a set of N-recognins for proteolysis via either the UPS or autophagy. The N-degron Cys mediates O2-dependent proteolysis through its oxidation and arginylation, which generates two structurally distinct N-degrons, leading to proteolysis by either the UPS or autophagy. Mammals and plants employ this unique chemical property of Nt-Cys to sense and react to acute and chronic hypoxia as well as oxidative stress by adjusting cellular concentrations of proteins carrying the N-degron Cys. The N-degron pathway is a degradative system in which the N-terminal residues of proteins modulate the half-lives of proteins and other cellular materials. The majority of amino acids in the genetic code have the potential to induce cis or trans degradation in diverse processes, which requires selective recognition between N-degrons and cognate N-recognins. Of particular interest is the Cys/N-degron branch, in which the N-terminal cysteine (Nt-Cys) induces proteolysis via either the ubiquitin (Ub)–proteasome system (UPS) or the autophagy–lysosome pathway (ALP), depending on physiological conditions. Recent studies provided new insights into the central role of Nt-Cys in sensing the fluctuating levels of oxygen and reactive oxygen species (ROS). Here, we discuss the components, regulations, and functions of the Cys/N-degron pathway. The N-degron pathway is a degradative system in which the N-terminal residues of proteins modulate the half-lives of proteins and other cellular materials. The majority of amino acids in the genetic code have the potential to induce cis or trans degradation in diverse processes, which requires selective recognition between N-degrons and cognate N-recognins. Of particular interest is the Cys/N-degron branch, in which the N-terminal cysteine (Nt-Cys) induces proteolysis via either the ubiquitin (Ub)–proteasome system (UPS) or the autophagy–lysosome pathway (ALP), depending on physiological conditions. Recent studies provided new insights into the central role of Nt-Cys in sensing the fluctuating levels of oxygen and reactive oxygen species (ROS). Here, we discuss the components, regulations, and functions of the Cys/N-degron pathway. degradation of a protein driven by the destabilizing activity of a built-in degron. part of the N-degron pathway in which Nt-Cys acts as a degradation determinant and generates the N-degron Arg through oxidation and arginylation. a protein that recognizes a specific substrate and accelerates the transfer of Ub from an E2 enzyme to the substrate. a class of degrons in which the N-terminal destabilizing residue is the major degradation determinant in substrate recognition. a recognition component of the N-degron pathway that recognizes N-degrons for degradation. an N-terminal degradation determinant whose modification can generate an N-degron. codegradation of an otherwise stable protein that occurs when another protein undergoes cis degradation. a ~70-residue zinc-finger motif that acts as a substrate recognition domain for type-1 substrates of the N-degron pathway.