Matsuo Kazuhiko, Nakajima Yoshiro, Shigeta Masaki, Kobayashi Daisuke, Sakaki Shinichiro, Inoue Satoshi, Takeshita Naoki, Ueyama Atsuko, Nishikawa Kousuke, Saba Rie, Yamasaki Hideya, Yamada Kei, Yokoyama Takahiko, Yashiro Kenta
Department of Anatomy and Developmental Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
PLoS One. 2025 Jul 9;20(7):e0325921. doi: 10.1371/journal.pone.0325921. eCollection 2025.
Nearly all differentiated mammalian cells possess primary cilia on their surface. Ciliary dysfunction causes ciliopathy in humans. Centrosomal protein 290 (CEP290), a ciliary protein implicated in ciliopathies, localizes to the ciliary base and the centrosome in ciliated cells. CEP290-related ciliopathies arise from molecular dysfunctions of the CEP290 molecule, exhibiting a diverse range of symptoms. Thus far, these disorders have been attributed to cilia-specific functional abnormalities of CEP290, reflecting the conventional view of its primary role within cilia. However, CEP290 is also expressed in proliferating non-ciliated cells and localizes to the centrosome, suggesting potential cilia-independent functions of CEP290 in the pathophysiology of these disorders. In this study, we investigated the cilia-independent functions of CEP290 in non-ciliated cells. Our findings reveal that the loss of Cep290 function impairs microtubule elongation due to malfunction of the microtubule organizing center. Notably, CEP290 forms a complex with adenomatous polyposis coli (APC), a protein that localizes to the centrosome and associates with microtubules. Importantly, reduced focal adhesion formation appears to underlie the phenotypic abnormalities observed in Cep290 knockout cells, including impaired collective cell migration, altered cell morphology, and reduced adhesive capacity to the extracellular matrix. The APC-CEP290 complex plays a consistent and crucial role in stabilizing a focal adhesion molecule, paxillin, at the leading edge in non-ciliated cells. These findings provide a novel framework for understanding the molecular mechanisms underlying ciliopathies, highlighting the importance of CEP290's cilia-independent functions.
几乎所有分化的哺乳动物细胞表面都有初级纤毛。纤毛功能障碍会导致人类患上纤毛病。中心体蛋白290（CEP290）是一种与纤毛病相关的纤毛蛋白，在有纤毛的细胞中定位于纤毛基部和中心体。与CEP290相关的纤毛病源于CEP290分子的分子功能障碍，表现出多种多样的症状。到目前为止，这些疾病被归因于CEP290在纤毛中的特异性功能异常，这反映了其在纤毛中主要作用的传统观点。然而，CEP290也在增殖的无纤毛细胞中表达，并定位于中心体，这表明CEP290在这些疾病的病理生理学中可能具有不依赖于纤毛的功能。在本研究中，我们研究了CEP290在无纤毛细胞中不依赖于纤毛的功能。我们的研究结果表明，Cep290功能的丧失会由于微管组织中心的功能故障而损害微管伸长。值得注意的是，CEP290与腺瘤性息肉病大肠杆菌（APC）形成复合物，APC是一种定位于中心体并与微管相关的蛋白质。重要的是，粘着斑形成减少似乎是Cep290基因敲除细胞中观察到的表型异常的基础，包括集体细胞迁移受损、细胞形态改变以及对细胞外基质的粘附能力降低。APC-CEP290复合物在稳定无纤毛细胞前缘的粘着斑分子桩蛋白方面发挥着一致且关键的作用。这些发现为理解纤毛病的分子机制提供了一个新的框架，突出了CEP290不依赖于纤毛的功能的重要性。
