初级纤毛是类似天线的细胞器，可以感知细胞外信号并充当信号中枢。纤毛功能障碍会导致一组异质性疾病，称为纤毛病综合征，影响大多数器官。纤毛分解是细胞失去纤毛的过程，人们对此知之甚少，但在疾病和细胞转化中经常观察到。在这里，我们揭示了 PI3Kα 信号酶在纤毛分解中的作用。正如在 PIK3CA 相关过度生长谱 (PROS) 和癌症中观察到的，遗传性 PI3Kα 过度激活在小鼠发育过程中诱导了类似纤毛病的表型。从机制上讲，PI3Kα 和 PI3Kβ 在分解刺激后在纤毛过渡区产生 PIP3 脂质。 PI3Kα 激活通过 PDK1/PKCι 激酶、CEP170 中心体蛋白和 KIF2A 微管解聚驱动蛋白的激酶信号轴启动纤毛分解。我们的数据表明，由 PI3Kα 激活引起的疾病可被视为“纤毛疾病”，这是最近定义的纤毛病子集，其中部分（但不是全部）临床表现由纤毛功能障碍引起。© 2024。作者）。

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 PIP3 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.© 2024. The Author(s).