Superchanneling, Regulation of Caspases, and Site-Specific Control of RNA

Project Summary/Abstract Regulated proteolysis by the ubiquitin-proteasome system (ubiquitin system) plays essential roles in a multitude of biological processes and has major ramifications for human health and disease, including illnesses that range from cancer and neurodegeneration to cardiovascular syndromes and defects of immunity. Our studies of the ubiquitin-proteasome system and ubiquitin-dependent N-degron pathways (previously called “N-end rule pathways”) over more than three decades were made possible, to a large extent, by the present grant (GM031530), currently in its 41st year of support. N-degron pathways recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, polyubiquitylate these proteins and thereby cause their degradation by the proteasome or autophagy. Recognition components of N-degron pathways, called N-recognins, are E3 ubiquitin ligases that can target N-degrons. One eukaryotic N-degron pathway, called the Arg/N-degron pathway, targets, in particular, specific unmodified Nt-residues of protein substrates. This GM031530 renewal application stems from our unpublished studies over the last ~2 years, and focuses on new, previously unexplored aspects of the Arg/N-degron pathway. Specific proposed studies address a coupling between a C-degron and stability of a protein’s mRNA, the new phenomenon of superchanneling in targeting specific degrons, and a functional (as well as mechanistic) link between human caspases and the Arg/N-degron pathway. Our studies of this universally present proteolytic system will contribute to advances in fundamental biology and may also lead to therapies for specific human diseases.