The N-degron pathway: From basic science to therapeutic applications

The N-degron pathway is a degradative system in which single N-terminal (Nt) amino acids regulate the half-lives of proteins and other biological materials. These determinants, called N-degrons, are recognized by N-recognins that link them to the ubiquitin (Ub)-proteasome system (UPS) or autophagy-lysosome system (ALS). In the UPS, the Arg/N-degron pathway targets the Nt-arginine (Nt-Arg) and other N-degrons to assemble Lys48 (K48)-linked Ub chains by UBR box N-recognins for proteasomal proteolysis. In the ALS, Arg/N-degrons are recognized by the N-recognin p62/SQSTSM-1/Sequestosome-1 to induce cis-degradation of substrates and trans-degradation of various cargoes such as protein aggregates and subcellular organelles. This crosstalk between the UPS and ALP involves reprogramming of the Ub code. Eukaryotic cells developed diverse ways to target all 20 principal amino acids for degradation. Here we discuss the components, regulation, and functions of the N-degron pathways, with an emphasis on the basic mechanisms and therapeutic applications of Arg/N-degrons and N-recognins.

Automated summary

The N-degron pathway is a degradative system that regulates protein and biological material half-lives through N-terminal amino acids called N-degrons. N-degrons are recognized by N-recognins, which link them to the ubiquitin-proteasome system (UPS) or autophagy-lysosome system (ALS). The UPS targets N-terminal arginine (Nt-Arg) and other N-degrons for proteasomal proteolysis, while the ALS induces degradation of substrates and various cargoes through N-recognition. This interaction involves reprogramming of the Ub code. Eukaryotic cells have developed diverse mechanisms for targeting all 20 amino acids for degradation. This article discusses the components, regulation, and functions of N-degron pathways, with a focus on Arg/N-degrons and N-recognins' basic mechanisms and therapeutic applications.