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.

SMAC/DIABLO 和 HTRA2 是线粒体蛋白，其氨基末端序列称为凋亡结合基序抑制剂 (IBM)，可结合并激活称为凋亡蛋白抑制剂 (IAP) 的泛素连接酶，从而释放细胞的凋亡潜能。IBM 包含四个残基的松散共有序列，与 IAP 的结合需要未修饰的氨基末端。密切相关的类似 IBM 的 N 末端存在于大约 5% 的人类蛋白质中。我们显示 N-α-乙酰转移酶 NatA 的抑制将这些神秘的 IBM 样序列转变为细胞裂解物中和体外非常有效的 IAP 粘合剂，并最终触发细胞凋亡。因此，NatA 底物中 IBM 样基序的氨基末端乙酰化保护它们免受 IAP 的影响。这种以前未被认识的关系表明氨基末端乙酰化通常可以防止人体细胞中的蛋白质降解。它还将 IAP 确定为针对后生动物中未乙酰化的流氓的一般质量控制机制的代理。