Proper control of gene expression levels upon various perturbations is a fundamental aspect of cellular robustness. Protein-level dosage compensation is one mechanism buffering perturbations to stoichiometry of multiprotein complexes through accelerated proteolysis of unassembled subunits. Although N-terminal acetylation- and ubiquitin-mediated proteasomal degradation by the Ac/N-end rule pathway enables selective compensation of excess subunits, it is unclear how widespread this pathway contributes to stoichiometry control. Here we report that dosage compensation depends only partially on the Ac/N-end rule pathway. Our analysis of genetic interactions between 18 subunits and 12 quality control factors in budding yeast demonstrated that multiple E3 ubiquitin ligases and N-acetyltransferases are involved in dosage compensation. We find that N-acetyltransferases-mediated compensation is not simply predictable from N-terminal sequence despite their sequence specificity for N-acetylation. We also find that the compensation of Pop3 and Bet4 is due in large part to a minor N-acetyltransferase NatD. Furthermore, canonical NatD substrates histone H2A/H4 were compensated even in its absence, suggesting N-acetylation-independent stoichiometry control. Our study reveals the complexity and robustness of the stoichiometry control system.

在各种扰动下正确控制基因表达水平是细胞健壮性的基本方面。蛋白质水平的剂量补偿是一种通过加速未组装亚基的蛋白水解作用来缓冲微蛋白质复合物化学计量扰动的机制。尽管通过Ac / N端规则途径进行的N端乙酰化和泛素介导的蛋白酶体降解能够选择性补偿过量的亚基，但尚不清楚该途径在多大程度上有助于化学计量控制。在这里，我们报告剂量补偿仅部分取决于Ac / N端规则途径。我们对发芽酵母中18个亚基和12个质量控制因子之间的遗传相互作用的分析表明，多种E3泛素连接酶和N-乙酰基转移酶参与剂量补偿。我们发现，尽管N-乙酰基转移酶对N-乙酰化具有序列特异性，但N-乙酰基转移酶介导的补偿不能简单地从N-末端序列预测。我们还发现，Pop3和Bet4的补偿很大程度上归因于较小的N-乙酰基转移酶NatD。此外，规范的NatD底物组蛋白H2A / H4即使在不存在的情况下也能得到补偿，这表明N-乙酰化无关的化学计量控制。我们的研究揭示了化学计量控制系统的复杂性和鲁棒性。提示不依赖于N-乙酰化的化学计量控制。我们的研究揭示了化学计量控制系统的复杂性和鲁棒性。提示不依赖于N-乙酰化的化学计量控制。我们的研究揭示了化学计量控制系统的复杂性和鲁棒性。