PHF23 (plant homeodomain finger protein 23) negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1

Autophagy is a multistep process that involves the degradation and digestion of intracellular components by the lysosome. It has been proved that many core autophagy-related molecules participate in this event. However, new component proteins that regulate autophagy are still being discovered. At present, we report PHF23 (PHD finger protein 23) with a PHD-like zinc finger domain that can negatively regulate autophagy. Data from experiments indicated that the overexpression of PHF23 impaired autophagy, as characterized by decreased levels of LC3B-II and weakened degradation of endogenous and exogenous autophagic substrates. Conversely, knockdown of <i>PHF23</i> resulted in opposite effects. Molecular mechanism studies suggested that PHF23 interacts with LRSAM1, which is an E3 ligase key for ubiquitin-dependent autophagy against invading bacteria. PHF23 promotes the ubiquitination and proteasome degradation of LRSAM1. We also show that the PHD finger of PHF23 is a functional domain needed for the interaction with LRSAM1. Altogether, our results indicate that PHF23 is a negative regulator associated in autophagy via the LRSAM1 signaling pathway. The physical and functional connection between the PHF23 and LRSAM1 needs further investigation.

自噬（Autophagy）是一类多步骤生物学过程，依赖溶酶体完成对细胞内组分的降解与消化。已有研究证实，多种核心自噬相关分子参与该进程。然而，调控自噬的新型组分蛋白仍持续被发掘。本研究报道，携带类PHD锌指结构域的PHF23（PHD finger protein 23）可负向调控自噬。实验数据显示，PHF23过表达会损伤自噬，具体表现为LC3B-II水平下降，内源性与外源性自噬底物的降解能力减弱。反之，敲低PHF23则会产生相反的生物学效应。分子机制研究表明，PHF23可与LRSAM1相互结合；LRSAM1是介导针对入侵细菌的泛素依赖型自噬的关键E3泛素连接酶。PHF23可促进LRSAM1的泛素化修饰与蛋白酶体降解。本研究同时证实，PHF23的PHD指结构域是其与LRSAM1相互作用所必需的功能结构域。综上，本研究结果表明，PHF23是通过LRSAM1信号通路参与自噬调控的负向调节因子。PHF23与LRSAM1之间的物理与功能关联仍有待进一步深入探究。