Cell Signalling, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
Proteomics Research Translational Technology Platform, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
Nat Commun. 2024 Aug 21;15(1):7181. doi: 10.1038/s41467-024-51354-1.
Primary cilia are antenna-like organelles which sense extracellular cues and act as signalling hubs. Cilia dysfunction causes a heterogeneous group of disorders known as ciliopathy syndromes affecting most organs. Cilia disassembly, the process by which cells lose their cilium, is poorly understood but frequently observed in disease and upon cell transformation. Here, we uncover a role for the PI3Kα signalling enzyme in cilia disassembly. Genetic PI3Kα-hyperactivation, as observed in PIK3CA-related overgrowth spectrum (PROS) and cancer, induced a ciliopathy-like phenotype during mouse development. Mechanistically, PI3Kα and PI3Kβ produce the PIP lipid at the cilia transition zone upon disassembly stimulation. PI3Kα activation initiates cilia disassembly through a kinase signalling axis via the PDK1/PKCι kinases, the CEP170 centrosomal protein and the KIF2A microtubule-depolymerising kinesin. Our data suggest diseases caused by PI3Kα-activation may be considered 'Disorders with Ciliary Contributions', a recently-defined subset of ciliopathies in which some, but not all, of the clinical manifestations result from cilia dysfunction.
原发性纤毛是一种类似天线的细胞器，能够感知细胞外的信号，并作为信号中心发挥作用。纤毛功能障碍会导致一组异质性疾病，即纤毛病综合征，影响大多数器官。纤毛解体，即细胞失去纤毛的过程，目前了解甚少，但在疾病和细胞转化中经常观察到。在这里，我们揭示了 PI3Kα 信号酶在纤毛解体中的作用。在 PIK3CA 相关过度生长谱（PROS）和癌症中观察到的遗传 PI3Kα 过度激活，在小鼠发育过程中诱导了一种纤毛病样表型。在机制上，PI3Kα 和 PI3Kβ 在纤毛解体刺激时在纤毛过渡区产生 PIP 脂质。PI3Kα 激活通过 PDK1/PKCι 激酶、CEP170 中心体蛋白和 KIF2A 微管解聚驱动蛋白，通过激酶信号轴启动纤毛解体。我们的数据表明，由 PI3Kα 激活引起的疾病可能被认为是“具有纤毛贡献的疾病”，这是最近定义的纤毛病的一个子集，其中一些但不是所有的临床表现都源于纤毛功能障碍。
