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

SMAC/DIABLO and HTRA2 are mitochondrial proteins whose amino-terminal sequences, known as inhibitor of apoptosis binding motifs (IBMs), bind and activate ubiquitin ligases known as inhibitor of apoptosis proteins (IAPs), unleashing a cell's apoptotic potential. IBMs comprise a four-residue, loose consensus sequence, and binding to IAPs requires an unmodified amino terminus. Closely related, IBM-like N termini are present in approximately 5% of human proteins. We show that suppression of the N-alpha-acetyltransferase NatA turns these cryptic IBM-like sequences into very efficient IAP binders in cell lysates and in vitro and ultimately triggers cellular apoptosis. Thus, amino-terminal acetylation of IBM-like motifs in NatA substrates shields them from IAPs. This previously unrecognized relationship suggests that amino-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.

Automated summary

This study reveals that by inhibiting the N-α-acetyltransferase NatA, proteins with IBM-like motifs can be transformed into efficient IAP binders, leading to cellular apoptosis. Thus, acetylation of the amino-terminal IBM-like motifs in NatA substrates serves as a protective mechanism against IAPs.