ESD通过调控FKBP25的非经典乙酰化促进自噬的分子机制

丝氨酸和苏氨酸残基乙酰化是近年来在真核生物中新发现的蛋白质翻译后修饰，催化该修饰的关键酶还未见报道，该修饰的生物学功能亦有待深入阐明。前期研究发现，酯酶D（esterase D，ESD）能促进细胞自噬，可通过与FK506结合蛋白25（FK506 binding protein 25, FKBP25）相互作用抑制mTOR活性，但ESD调控FKBP25活性的分子机制有待阐明。本项目拟在鉴定FKBP25乙酰化修饰位点基础上，利用定点突变和质谱等技术重点探究ESD通过促进FKBP25的去乙酰化修饰从而调控mTOR活性和自噬的分子机制，证明ESD作为丝氨酸/苏氨酸去乙酰化酶介导ESD/FKBP25/mTORC1信号通路。本项目的实施不仅有助于阐明ESD调节mTORC1活性和细胞自噬的分子机制，还可能证明ESD是调控丝氨酸和苏氨酸残基乙酰化的关键酶，对理解该翻译后修饰的生物学功能具有重要意义。

Acetylation of serine/threonine residue is a newly discovered protein post-translational modification in recent years. It remains unknown about the key enzymes that catalyze this acetylation and the biological functions that this acetylation plays in eukaryotes. The previous study found that the esterase D (ESD) not only promoted cell autophagy, but also interacted with FK506 binding protein 25 (FKBP25) to suppress mTOR activity. However, the molecular mechanism by which the ESD regulates the FKBP25 activity remains elusive. In this proposal, we plan to identify the site of FKBP25 acetylation and then focus on the molecular mechanism that ESD could hydrolyze the acetylation modification of FKBP25 to promote autophagy via suppressing the activity of mTORC1 by mass spectrum and site-directed mutation and so on, and also prove that ESD serves as a serine or threonine deacetylase to mediate ESD/FKBP25/mTORC1 signal pathway. Our results will not only help to elucidate the molecular mechanism by which the ESD regulates mTORC1 and autophagy, but also to identify and uncover the key enzymes that involved in regulating the acetylation of serine and threonine residues, which has important scientific significance for understanding the biological function of this new posttranslational modification.