Overlap of NatA and IAP substrates implicates N-terminal acetyltion in protein stabilization

SMAC/DIABLO and HTRA2 are mitochondrial proteins whose N-termina sequences, known as inhibitor of apoptosis binding motifs (IBMs), bind and activate ubiquitin ligases knwon as inhibitor of apoptosis proteins (IAPs), unleashing a cell´s poteintial.IBMs comprise a 4-residue, loose consensus sequence, and binding to IAPs requires an unmodified N-terminus. Closely related, IBM-like N-termini, are present in approximately 5% of human proteins. We show that suppression of the N-alpha-acetytransferase NatA truns these cryptic IBM-like sequences into very efficient IAP binders in cell lysates and in vitro, and ultimately also triggers apoptosis. Thus, N-terminal acetylation of IBM-like motifs in NatA substrates shields them from IAPs. This previously unrecognized relatonship suggests that N-terminal acetylation is generally protective against protein degradation in human cells. It also identifies IAPs as agents of a general quality control mechanism targeting unacetylated rogues in metazoans