Big fish, little fish: N-terminal acetyltransferase Naa40p proteoforms caught in the act

Veronique Jonckheere, Petra Van Damme
2021 · doi:10.1101/2021.02.26.433048
preprint OA: closed
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Abstract

NatD consist of the evolutionary conserved N-alpha acetyltransferase catalytic subunit Naa40p and is among the most selective N-terminal acetyltransferase (NAT) complexes identified to date. Here we identified a conserved 22 amino acid N-terminally truncated Naa40 proteoform named Naa40p25 or short Naa40 (Naa40 S ). Intriguingly, while upon ectopic expression in yeast, both Naa40p proteoforms were capable of restoring N-terminal acetylation of the well characterized yeast histone H2A Naa40p substrate, the Naa40p histone H4 substrate remained N-terminally free in human haploid cells specifically deleted for canonical Naa40p27 or 237 amino acid long Naa40 (Naa40 L ), but expressing Naa40 S . Interestingly, human Naa40 L and Naa40 S displayed differential expression and subcellular localization patterns by exhibiting a principal nuclear and cytoplasmic localization, respectively. Further, since Naa40 L was identified as being N-terminally myristoylated and shown to interact with N-myristoyltransferase 1 (NMT1), NMT1 may steer Naa40 L nuclear import. Differential interactomics data obtained by biotin-dependent proximity labeling (BioID) further hints to context dependent roles of Naa40p proteoforms. More specifically, with Naa40 S representing the main co-translationally acting actor, the interactome of Naa40 L was enriched for nucleolar proteins implicated in ribosome biogenesis and the assembly of ribonucleoprotein particles, overall indicating a proteoform-specific segregation of previously reported Naa40p activities. Finally, the yeast histone variant H2A.Z and the transcriptionally regulatory protein Lge1 were identified as novel Naa40p substrates, expanding the restricted substrate repertoire of Naa40p with two additional members and further confirming Lge1 as being the first redundant yNatA and yNatD substrate identified to date.

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