Department of Biomedicine, University of Bergen, N-5021, Bergen, Norway.
Department of Biological Sciences, University of Bergen, N-5006, Bergen, Norway.
Nat Commun. 2023 Oct 27;14(1):6774. doi: 10.1038/s41467-023-42342-y.
Most eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in human cells, we reveal a strong genetic dependency between a major N-terminal acetyltransferase and specific ubiquitin ligases. Biochemical analyses uncover that both the ubiquitin ligase complex UBR4-KCMF1 and the acetyltransferase NatC recognize proteins bearing an unacetylated N-terminal methionine followed by a hydrophobic residue. NatC KO-induced protein degradation and phenotypes are reversed by UBR knockdown, demonstrating the central cellular role of this interplay. We reveal that loss of Drosophila NatC is associated with male sterility, reduced longevity, and age-dependent loss of motility due to developmental muscle defects. Remarkably, muscle-specific overexpression of UbcE2M, one of the proteins targeted for NatC KO-mediated degradation, suppresses defects of NatC deletion. In conclusion, NatC-mediated N-terminal acetylation acts as a protective mechanism against protein degradation, which is relevant for increased longevity and motility.
大多数真核生物蛋白质的 N 端被乙酰化，但这种修饰在全局范围内的功能影响仍不清楚。我们在人类细胞中使用全基因组 CRISPR 敲除筛选，揭示了主要的 N 端乙酰转移酶和特定泛素连接酶之间存在强烈的遗传依赖性。生化分析揭示，泛素连接酶复合物 UBR4-KCMF1 和乙酰转移酶 NatC 都能识别带有未乙酰化的 N 端甲硫氨酸和疏水性残基的蛋白质。NatC KO 诱导的蛋白降解和表型可通过 UBR 敲低逆转，证明了这种相互作用在细胞中的核心作用。我们发现果蝇 NatC 的缺失与雄性不育、寿命缩短以及由于发育性肌肉缺陷导致的年龄依赖性运动能力丧失有关。值得注意的是，肌肉特异性过表达 UbcE2M（NatC KO 介导的降解所针对的蛋白质之一）可抑制 NatC 缺失的缺陷。总之，NatC 介导的 N 端乙酰化作为一种防止蛋白降解的保护机制，与寿命延长和运动能力增强有关。
