Control of Protein Quality and Stoichiometries by N-Terminal Acetylation and the N-End Rule Pathway

SummaryNα-terminal acetylation of cellular proteins was recently discovered to create specific degradation signals termed Ac/N-degrons and targeted by the Ac/N-end rule pathway. We show that Hcn1, a subunit of the APC/C ubiquitin ligase, contains an Ac/N-degron that is repressed by Cut9, another APC/C subunit and the ligand of Hcn1. Cog1, a subunit of the Golgi-associated COG complex, is also shown to contain an Ac/N-degron. Cog2 and Cog3, direct ligands of Cog1, can repress this degron. The subunit decoy technique was used to show that the long-lived endogenous Cog1 is destabilized and destroyed via its activated (unshielded) Ac/N-degron if the total level of Cog1 increased in a cell. Hcn1 and Cog1 are the first examples of protein regulation through the physiologically relevant transitions that shield and unshield natural Ac/N-degrons. This mechanistically straightforward circuit can employ the demonstrated conditionality of Ac/N-degrons to regulate subunit stoichiometries and other aspects of protein quality control.

► N-terminal acetylation of cellular proteins can create specific Ac/N-degrons
► Hcn1 and Cog1 are shown to contain specific Ac/N-degrons
► Ac/N-degrons of Cog1 and Hcn1 are repressed by their ligands Cog2/3 and Cut9
► Conditionality of Ac/N-degrons can mediate the control of protein stoichiometries