N-terminal acetylation of proteins by NatA and NatB serves distinct physiological roles in Saccharomyces cerevisiae.

N-terminal (Nt) acetylation is a highly prevalent co-translational protein modification in eukaryotes, catalyzed by at least five Nt acetyltransferases (Nats) with differing specificities. Nt acetylation has been implicated in protein quality control, but its broad biological significance remains elusive. We investigate the roles of the two major Nats of S. cerevisiae, NatA and NatB, by performing transcriptome, translatome, and proteome profiling of natAΔ and natBΔ mutants. Our results reveal a range of NatA- and NatB-specific phenotypes. NatA is implicated in systemic adaptation control, because natAΔ mutants display altered expression of transposons, sub-telomeric genes, pheromone response genes, and nuclear genes encoding mitochondrial ribosomal proteins. NatB predominantly affects protein folding, because natBΔ mutants, to a greater extent than natA mutants, accumulate protein aggregates, induce stress responses, and display reduced fitness in the absence of the ribosome-associated chaperone Ssb. These phenotypic differences indicate that controlling Nat activities may serve to elicit distinct cellular responses.