Abstract
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.
Highlights
Controlling intracellular protein concentration at the proper level is a critical aspect of cellular systems
Quality control of multiprotein complexes is important for maintaining homeostasis in cellular systems that are based on functional complexes
Protein N-terminal acetylation- and ubiquitin-mediated proteolysis pathway is involved in selective degradation of excess subunits, it is unclear how widespread this pathway contributes to stoichiometry control due to the lack of a systematic investigation using endogenous proteins
Summary
Controlling intracellular protein concentration at the proper level is a critical aspect of cellular systems. Genome-wide studies measuring cellular robustness against genetic perturbations showed that Saccharomyces cerevisiae cells are fragile against protein overexpression of a subset of the genome [4, 5]. This finding indicates that the cell system is generally robust against genetic perturbations to various biological processes. Comprehensive analyses of aneuploid yeast and mammalian cells showed that approximately 20% of the genome exhibit this molecular phenotype [8, 9] This phenomenon known as protein-level dosage compensation may partially explain the buffering of gene expression perturbations
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