Control of protein degradation by N-terminal acetylation and the N-end rule pathway

Nα-terminal acetylation (Nt-acetylation) occurs very frequently and is found in most proteins in eukaryotes. Despite the pervasiveness and universality of Nt-acetylation, its general functions in terms of physiological outcomes remain largely elusive. However, several recent studies have revealed that Nt-acetylation has a significant impact on protein stability, activity, folding patterns, cellular localization, etc. In addition, Nt-acetylation marks specific proteins for degradation by a branch of the N-end rule pathway, a subset of the ubiquitin-mediated proteolytic system. The N-end rule associates a protein’s in vivo half-life with its N-terminal residue or modifications on its N-terminus. This review provides a current understanding of intracellular proteolysis control by Nt-acetylation and the N-end rule pathway. The addition of an acetyl group to amino acids at the start of a protein (known as the Nα-terminal end) is crucial for maintaining protein homeostasis and cellular health. Hwang and colleagues review the effects of Nα-terminal acetylation (Nt-acetylation) on protein function and stability. This modification occurs in over 50% of proteins in eukaryotic organisms and when mis-regulated can lead to cancer, hypertension, neurodegeneration etc. Nt-acetylation not only targets proteins for degradation through a specific signaling pathway, but also regulates protein folding, cellular localization and activity. This seemingly irreversible modification can also protect proteins against other mechanisms of degradation and represents a potential therapeutic target. Inhibiting Nt-acetylation-dependent protein interactions could be a useful strategy for regulating protein stability.