EHD1 promotes CP110 ubiquitination by centriolar satellite delivery of HERC2 to the mother centriole

Primary cilia are sensory organelles that coordinate diverse signaling pathways, controlling development and homeostasis. Progression beyond the early steps of ciliogenesis requires removal of a distal end protein, CP110, from the mother centriole, a process mediated by Eps15 Homology Domain protein 1 (EHD1). We show that EHD1 regulates CP110 ubiquitination during ciliogenesis, and identify two E3 ubiquitin ligases, HECT domain and RCC1-like domain 2 (HERC2) and mindbomb homolog 1 (MIB1), that interact with and ubiquitinate CP110. We determined that HERC2 is required for ciliogenesis and localizes to centriolar satellites, which are peripheral aggregates of centriolar proteins known to regulate ciliogenesis. We reveal a role for EHD1 in the transport of centriolar satellites and HERC2 to the mother centriole during ciliogenesis. Taken together, our work showcases a mechanism whereby EHD1 controls centriolar satellite movement to the mother centriole, thus delivering the E3 ubiquitin ligase HERC2 to promote CP110 ubiquitination and degradation.

初级纤毛（Primary cilia）是一类感知细胞器，可协调多种信号通路，调控机体发育与内环境稳态。纤毛发生的早期步骤完成后，需将母中心粒上的远端末端蛋白CP110移除，这一过程由Eps15同源结构域蛋白1（EHD1）介导。本研究证实，EHD1可在纤毛发生过程中调控CP110的泛素化，并鉴定出两种可与CP110相互作用并对其进行泛素化修饰的E3泛素连接酶：HECT结构域与RCC1样结构域2（HERC2）以及mindbomb同源物1（MIB1）。研究发现，HERC2是纤毛发生所必需的蛋白，且定位于中心粒卫星——一类已知可调控纤毛发生的中心粒蛋白外周聚集物。本研究还揭示，EHD1在纤毛发生过程中参与中心粒卫星及HERC2向母中心粒的转运。综上，本研究阐明了一套全新的调控机制：EHD1通过介导中心粒卫星向母中心粒的移动，递送E3泛素连接酶HERC2，进而促进CP110的泛素化修饰与降解。