The SESAME complex regulates cell senescence through the generation of acetyl-CoA
The SESAME complex regulates cell senescence through the generation of acetyl-CoA
复制标题
SESAME 复合物通过乙酰辅酶 A 的生成调节细胞衰老
DOI：
10.1038/s42255-021-00412-9
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发表时间：
2021-06-28
影响因子：
20.8
通讯作者：
Li, Shanshan
中科院分区：
文献类型：
--
作者：
Chen, Wanping;Yu, Xilan;Li, Shanshan
乙酰辅酶a是碳代谢的中心节点，在调节和生物合成过程中起关键作用。乙酰辅酶a合成酶Acs2是含丝氨酸响应sam代谢酶（SESAME）复合体的一个完整亚基，它催化醋酸酯生成乙酰辅酶a，但Acs2在SESAME复合体中的确切功能尚不清楚。在这里，我们使用出芽酵母，证明了SESAME复合体中的Acs2是端粒沉默和细胞衰老调控所必需的。在机制上，SESAME复合物与组蛋白乙酰转移酶SAS蛋白复合物相互作用，促进组蛋白H4K16乙酰化（H4K16ac）富集，并在亚端粒区域占据含溴结构域蛋白Bdf1。这种相互作用通过拮抗Sir2沿端粒的扩散来维持端粒沉默，这是由醋酸增强的。因此，端粒中Sir2的醋酸解离导致端粒沉默受损和加速时间老化。在人内皮细胞中，ACSS2，酵母Acs2的同源物，也与H4K16乙酰转移酶hMOF相互作用，并且是醋酸增加H4K16ac，减少端粒沉默和诱导细胞衰老所必需的。总之，我们的研究结果揭示了一种将细胞代谢与端粒沉默和细胞衰老联系起来的保守机制。
Acetyl-CoA is a central node in carbon metabolism and plays critical roles in regulatory and biosynthetic processes. The acetyl-CoA synthetase Acs2, which catalyses acetyl-CoA production from acetate, is an integral subunit of the serine-responsive SAM-containing metabolic enzyme (SESAME) complex, but the precise function of Acs2 within the SESAME complex remains unclear. Here, using budding yeast, we show that Acs2 within the SESAME complex is required for the regulation of telomere silencing and cellular senescence. Mechanistically, the SESAME complex interacts with the histone acetyltransferase SAS protein complex to promote histone H4K16 acetylation (H4K16ac) enrichment and the occupancy of bromodomain-containing protein, Bdf1, at subtelomeric regions. This interaction maintains telomere silencing by antagonizing the spreading of Sir2 along the telomeres, which is enhanced by acetate. Consequently, dissociation of Sir2 from telomeres by acetate leads to compromised telomere silencing and accelerated chronological ageing. In human endothelial cells, ACSS2, the ortholog of yeast Acs2, also interacts with H4K16 acetyltransferase hMOF and are required for acetate to increase H4K16ac, reduce telomere silencing and induce cell senescence. Altogether, our results reveal a conserved mechanism to connect cell metabolism with telomere silencing and cellular senescence.