Abstract
N-terminal acetylation (Nt-acetylation) is a highly abundant protein modification in eukaryotes and impacts a wide range of cellular processes, including protein quality control and stress tolerance. Despite its prevalence, the mechanisms regulating Nt-acetylation are still nebulous. Here, we present the first global study of Nt-acetylation in yeast cells as they progress to stationary phase in response to nutrient starvation. Surprisingly, we found that yeast cells maintain their global Nt-acetylation levels upon nutrient depletion, despite a marked decrease in acetyl-CoA levels. We further observed two distinct sets of protein N termini that display differential and opposing Nt-acetylation behavior upon nutrient starvation, indicating a dynamic process. The first protein cluster was enriched for annotated N termini showing increased Nt-acetylation in stationary phase compared with exponential growth phase. The second protein cluster was conversely enriched for alternative nonannotated N termini (i.e. N termini indicative of shorter N-terminal proteoforms) and, like histones, showed reduced acetylation levels in stationary phase when acetyl-CoA levels were low. Notably, the degree of Nt-acetylation of Pcl8, a negative regulator of glycogen biosynthesis and two components of the pre-ribosome complex (Rsa3 and Rpl7a) increased during starvation. Moreover, the steady-state levels of these proteins were regulated both by starvation and NatA activity. In summary, this study represents the first comprehensive analysis of metabolic regulation of Nt-acetylation and reveals that specific, rather than global, Nt-acetylation events are subject to metabolic regulation.
Highlights
N-terminal acetylation (Nt-acetylation) is a highly abundant protein modification in eukaryotes and impacts a wide range of cellular processes, including protein quality control and stress tolerance
Histone Acetylation is Sensitive to acetylation of N termini (Acetyl)-CoA Levels—Previous research has shown that histone acetylation is sensitive to acetyl-CoA availability (28 –31), indicating that protein acetylation in general could be dynamic with respect to cellular metabolism
We found that the steady-state levels of Nt-acetylation of database annotated N termini remained fairly stable following entry into stationary phase, despite a prominent decrease in acetyl-CoA and histone acetylation levels (Fig 2A)
Summary
Nt-acetylation is a prevalent protein modification catalyzed by N-terminal acetyltransferases using acetyl-CoA as acetyl donor. Friis and colleagues demonstrated that refeeding yeast cells in stationary phase can temporary restore histone acetylation levels This effect is mainly mediated by the untargeted activity of Piccolo NuA4 and SAGA complexes and relies on glycolysis. The findings linking cellular metabolism to global histone acetylation (29 –31) and the fact that many proteins are only partially Nt-acetylated [4] suggest that the NAT machinery might respond to metabolic cues. To address this hypothesis, we examined the effect of altered cellular metabolism on the global level of Nt-acetylation in the budding yeast Saccharomyces cerevisiae.
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