Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation

Telomeres are organized into a heterochromatin structure and maintenance of silent heterochromatin is required for chromosome stability. How telomere heterochromatin is dynamically regulated in response to stimuli remains unknown. Pyruvate kinase Pyk1 forms a complex, named SESAME (Serine-responsive SAM-containing Metabolic Enzyme complex) to regulate gene expression by phosphorylating histone H3T11 (H3pT11). Here, we identified a novel function of SESAME in regulating telomere heterochromatin structure. SESAME phosphorylates H3T11 at telomeres, which promotes SIR (silent information regulator) complex assembly at telomeres and protects Sir2 from degradation by autophagy. Moreover, SESAMEcatalyzed H3pT11 directly represses autophagy-related gene expression to further prevent autophagy-mediated Sir2 degradation. By promoting H3pT11, serine increases Sir2 protein levels and enhances telomere silencing. Loss of H3pT11 leads to reduced Sir2 and compromised telomere silencing during chronological aging. Together, our study provides insights into dynamic regulation of silent heterochromatin by histone modifications and autophagy in response to cell metabolism and aging.端粒（Telomeres）组装形成异染色质（heterochromatin）结构，维持沉默型异染色质的稳态对于染色体稳定性（chromosome stability）不可或缺。目前，端粒异染色质如何响应刺激发生动态调控仍未明确。丙酮酸激酶Pyk1可形成一种被命名为丝氨酸响应型含SAM代谢酶复合物（Serine-responsive SAM-containing Metabolic Enzyme complex，简称SESAME）的复合物，通过磷酸化组蛋白H3T11（histone H3T11，H3pT11）调控基因表达。本研究首次揭示了SESAME在调控端粒异染色质结构中的全新功能：SESAME可在端粒位点磷酸化H3pT11，该修饰可促进沉默信息调节因子复合物（silent information regulator complex，简称SIR复合物）在端粒处的组装，并保护Sir2免受自噬（autophagy）介导的降解。此外，SESAME催化产生的H3pT11还可直接抑制自噬相关基因的表达，进一步阻断自噬依赖的Sir2降解途径。通过促进H3T11磷酸化，丝氨酸可提升Sir2蛋白水平并增强端粒沉默效应。在时序衰老（chronological aging）过程中，H3T11磷酸化缺失会导致Sir2水平降低，并削弱端粒沉默功能。综上，本研究阐明了组蛋白修饰与自噬如何响应细胞代谢与衰老进程，进而动态调控沉默型异染色质的分子机制。