线粒体通过分裂/融合改变形态以适应环境变化。线粒体分裂需要内质网协作，管状内质网在线粒体分裂起始点形成缠绕，促使局部收缩，并逐步召募分裂相关蛋白，最终将线粒体一分为二。INF2是位于内质网的Formin蛋白，在内质网-线粒体互作中促进微丝聚合，帮助分裂。前期工作中我们发现E3泛素连接酶SPOP介导INF2的非降解型泛素化修饰，促进其从内质网转运到胞浆，抑制内质网参与的线粒体分裂（PLoS Genet, 2017）；而去泛素化酶USP10可以拮抗SPOP对INF2的泛素化；能量压力下AMPK激酶可以磷酸化INF2及USP10。本项目将重点研究能量压力下AMPK/USP10/SPOP调控网络通过磷酸化及（去）泛素化修饰，调节INF2定位及活性，影响内质网-线粒体互作及线粒体分裂的分子机制；并以SPOP高频突变的子宫内膜癌为模型，研究INF2翻译后修饰紊乱导致内质网-线粒体互作失调的病理学意义

Mitochondria undergo dynamic morphological changes (fission-fusion balance) to adapt to the environment changes. Mitochondrial division requires the cooperation of endoplasmic reticulum. Mitochondrial division occurred at positions where ER tubules contacted mitochondria and mediated constriction before recruitment of fission-associated factors. INF2 is an endoplasmic reticulum-localized Formin protein, promotes actin polymerization at the endoplasmic reticulum-mitochondrial contact sites to facilitate mitochondrial fission. In previous work we found that the E3 ubiquitin ligase SPOP mediates the non-degradative ubiquitination of INF2 and promotes the transport of INF2 from the endoplasmic reticulum to the cytosol, thereby inhibiting INF2-dependent mitochondrial division (PLoS Genet, 2017). The deubiquitinase USP10 can antagonize SPOP-mediated INF2 ubiquitination. Under energy stress AMPK phosphorylates INF2 and USP10. Our project aims to investigate the molecular mechanism of AMPK/USP10/SPOP regulatory network-mediated INF2 phosphorylation and (de) ubiquitination in response to energy stress. The pathological significance of endoplasmic reticulum-mitochondrial interaction dysregulation caused by INF2 post-translational modification disorder will be studied in endometrial cancer settings.