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

• Published in: Trends in cell biology 2023-03, Vol.33 (3), p.247-259
• Main Authors: Heo, Ah Jung, Ji, Chang Hoon, Kwon, Yong Tae
• Format: Article
• Language: English
• Subjects: Autophagy; Cysteine - metabolism; Humans; N-recognin; N-terminal oxidation; oxygen sensor; Proteasome Endopeptidase Complex - metabolism; Proteolysis; the N-degron pathway; Ubiquitin - metabolism
• ISSN: 0962-8924; 1879-3088
• DOI: 10.1016/j.tcb.2022.07.005

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. 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.