PDF(Pubmed)
Abstract：
Autophagy is a catabolic process to maintain homeostasis, and involved in cell differentiation and development. Autophagy is tightly regulated in response to nutrient availability but the underlying mechanism is not completely understood. Recently, we identified the chromatin remodeling complex INO80 (inositol-requiring mutant 80) and histone variant H2A.Z as new autophagy regulators and uncover how histone deacetylase Rpd3L (reduced potassium dependency 3 large) complex represses autophagy by deacetylating Ino80 and H2A.Z. In particular, Rpd3L complex deacetylates Ino80 at lysine 929, which protects Ino80 from being degraded by autophagy. The stabilized Ino80 then evicts H2A.Z from autophagy-related (ATG) genes, leading to their transcriptional repression. In parallel, Rpd3L complex also deacetylates H2A.Z, which further reduces its association with ATG gene promoters and repress ATG gene transcription. Under nutrient-rich conditions, Rpd3L-mediated deacetylation of Ino80 K929 and H2A.Z is enhanced by the TORC1 complex (target of rapamycin complex 1). Under nitrogen-starvation condition, TORC1 is inactivated, leading to reduced activity of Rpd3L complex and increased acetylation of Ino80 and H2A.Z, which in turn induce the transcription of ATG genes. These results reveal a critical role of chromatin remodelers and histone variants in regulating autophagy in response to nutrient availability.Abbreviations: INO80: inositol-requiring mutant 80; Rpd3: reduced potassium dependency 3; H2A.Z: histone H2A variant; Rpd3L complex: Rpd3 large complex; H4K16: H4 lysine 16; H3R17: H3 arginine 17; H3T11: H3 threonine 11; TORC1 complex: target of rapamycin complex 1; ATG: autophagy-related; SWI/SNF: switch/sucrose non-fermentable; SWR1: Swi2/Snf2-related ATPase complex; RSC: remodel the structure of chromatin; ISWI: imitation switch; CHD1: chromodomain helicase DNA binding protein 1; Arp8: actin-related protein 8; Sds3: suppressor of defective silencing 3; Ume6: unscheduled meiotic gene expression 6.
摘要：
自噬是维持体内平衡的分解代谢过程，并参与细胞分化和发育。自噬在响应营养可用性时受到严格调节，但其潜在机制尚未完全了解。最近,我们鉴定了染色质重塑复合物INO80(需要肌醇的突变体80)和组蛋白变异体H2A.Z作为新的自噬调节剂，并揭示了组蛋白脱乙酰酶Rpd3L（减少钾依赖性3大）复合物如何通过脱乙酰Ino80和H2A.Z抑制自噬。Rpd3L复合物在赖氨酸929处使Ino80脱乙酰，从而保护Ino80免于被自噬降解。然后稳定的Ino80驱逐H2A。来自自噬相关（ATG）基因的Z，导致它们的转录抑制。并行,Rpd3L络合物也使H2A脱乙酰化。Z,进一步减少其与ATG基因启动子的关联并抑制ATG基因转录。在营养丰富的条件下，Rpd3L介导的Ino80K929和H2A的脱乙酰化。Z被TORC1复合物(雷帕霉素复合物1的靶标)增强。在氮饥饿条件下，TORC1是灭活的,导致Rpd3L复合物的活性降低和Ino80和H2A的乙酰化增加。Z,进而诱导ATG基因的转录。这些结果揭示了染色质重塑剂和组蛋白变体在调节响应营养可用性的自噬中的关键作用。缩写:INO80:需要肌醇的突变体80;Rpd3:降低的钾依赖性3;H2A。Z：组蛋白H2A变体；Rpd3L复合物：Rpd3大复合物；H4K16：H4赖氨酸16；H3R17：H3精氨酸17；H3T11：H3苏氨酸11；TORC1复合物：雷帕霉素复合物1的靶标；ATG：自噬相关；SWI/SNF：开关/蔗糖不可发酵；SWI/SNF：switch/蔗糖非发酵；SWR1基因：与表达的
