Lysine acetyltransferase NuA4 and acetyl-CoA regulate glucose-deprived stress granule formation in Saccharomyces cerevisiae

Eukaryotic cells form stress granules under a variety of stresses, however the signaling pathways regulating their formation remain largely unknown. We have determined that the Saccharomyces cerevisiae lysine acetyltransferase complex NuA4 is required for stress granule formation upon glucose deprivation but not heat stress. Further, the Tip60 complex, the human homolog of the NuA4 complex, is required for stress granule formation in cancer cell lines. Surprisingly, the impact of NuA4 on glucose-deprived stress granule formation is partially mediated through regulation of acetyl-CoA levels, which are elevated in NuA4 mutants. While elevated acetyl-CoA levels suppress the formation of glucose-deprived stress granules, decreased acetyl-CoA levels enhance stress granule formation upon glucose deprivation. Further our work suggests that NuA4 regulates acetyl-CoA levels through the Acetyl-CoA carboxylase Acc1. Altogether this work establishes both NuA4 and the metabolite acetyl-CoA as critical signaling pathways regulating the formation of glucose-deprived stress granules.

真核细胞在多种应激条件下均可形成应激颗粒（stress granules），然而调控其形成的信号通路迄今仍未完全阐明。本研究证实，酿酒酵母（Saccharomyces cerevisiae）的赖氨酸乙酰转移酶复合物NuA4是葡萄糖剥夺条件下应激颗粒形成的必需复合物，但并非热应激下应激颗粒形成所必需。此外，NuA4复合物的人类同源物Tip60复合物，是癌细胞系中应激颗粒形成的必需复合物。令人意外的是，NuA4对葡萄糖剥夺诱导的应激颗粒形成的调控作用，部分通过调控乙酰辅酶A（acetyl-CoA）的水平实现：NuA4突变体中乙酰辅酶A水平显著升高。乙酰辅酶A水平升高会抑制葡萄糖剥夺诱导的应激颗粒形成，而乙酰辅酶A水平降低则会促进该条件下的应激颗粒形成。本研究进一步表明，NuA4通过乙酰辅酶A羧化酶Acc1调控乙酰辅酶A的水平。综上，本研究确立了NuA4及其调控的代谢物乙酰辅酶A，作为调控葡萄糖剥夺诱导的应激颗粒形成的关键信号通路调控元件。