Perilipin 2 (PLIN2) is a major lipid droplet (LD)-associated protein that regulates intracellular lipid homeostasis and LD formation. Under lipid-deprived conditions, the LD-unbound (free) form of PLIN2 is eliminated in the cytosol by an as yet unknown ubiquitin (Ub)-proteasome pathway that is associated with the N-terminal or near N-terminal residues of the protein.Here, using HeLa, HEK293T, and HepG2 human cell lines, cycloheximide chase, in vivo ubiquitylation, split-Ub yeast twohybrid, and chemical cross-linking-based reciprocal co-immunoprecipitation assays, we found that TEB4 (MARCH6), an E3 Ub ligase and recognition component of the Ac/N-end rule pathway, directly targets the N-terminal acetyl moiety of N␣-terminally acetylated PLIN2 for its polyubiquitylation and degradation by the 26S proteasome. We also show that the TEB4-mediated Ac/N-end rule pathway reduces intracellular LD accumulation by degrading PLIN2. Collectively, these findings identify PLIN2 as a substrate of the Ac/N-end rule pathway and indicate a previously unappreciated role of the Ac/N-end rule pathway in LD metabolism.

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.

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