Dewanji Rahit, Naslavsky Naava, Caplan Steve
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198.
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198.
Mol Biol Cell. 2025 Mar 1;36(3):br7. doi: 10.1091/mbc.E24-10-0455. Epub 2025 Jan 9.
The primary cilium is a crucial signaling organelle that can be generated by most human cells, and impediments to primary ciliogenesis lead to a variety of developmental disorders known as ciliopathies. The removal of the capping protein, CP110, from the mother centriole is a key early step that promotes generation of the ciliary vesicle and ciliogenesis. Recent studies have demonstrated that CP110 undergoes polyubiquitination and degradation in the proteosome, but the mechanisms of unfolding and removal from the mother centriole remain unknown. Herein we demonstrate that p97/Valosin-containing protein (VCP or Cdc48), a member of the ATPase Associated with diverse Activities (AAA) protein family, is responsible for removal of CP110 from the mother centriole. We show that use of p97 knockdown or inhibition impairs ciliogenesis, in a mechanism dependent on CP110. Our findings demonstrate a novel role for p97 in the process of primary ciliogenesis, and support a mechanism by which ubiquitinated CP110 is degraded in a process that requires p97-mediated unfolding and removal from the mother centriole.
初级纤毛是一种重要的信号细胞器，大多数人类细胞都能产生，而初级纤毛发生的障碍会导致多种被称为纤毛病的发育障碍。从母中心粒去除帽蛋白CP110是促进睫泡生成和纤毛发生的关键早期步骤。最近的研究表明，CP110在蛋白酶体中发生多聚泛素化和降解，但其从母中心粒展开和去除的机制仍不清楚。在此，我们证明了与多种活性相关的ATP酶（AAA）蛋白家族成员p97/含缬酪肽蛋白（VCP或Cdc48）负责从母中心粒去除CP110。我们表明，使用p97基因敲低或抑制会损害纤毛发生，其机制依赖于CP110。我们的研究结果证明了p97在初级纤毛发生过程中的新作用，并支持一种机制，即泛素化的CP110在一个需要p97介导的从母中心粒展开和去除的过程中被降解。
