Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization.
Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization.
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DOI：
10.1038/ncomms9666
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发表时间：
2015-10-21
影响因子：
16.6
通讯作者：
Saunier S
中科院分区：
文献类型：
--
作者：
Bizet AA;Becker-Heck A;Ryan R;Weber K;Filhol E;Krug P;Halbritter J;Delous M;Lasbennes MC;Linghu B;Oakeley EJ;Zarhrate M;Nitschké P;Garfa-Traore M;Serluca F;Yang F;Bouwmeester T;Pinson L;Cassuto E;Dubot P;Elshakhs NAS;Sahel JA;Salomon R;Drummond IA;Gubler MC;Antignac C;Chibout S;Szustakowski JD;Hildebrandt F;Lorentzen E;Sailer AW;Benmerah A;Saint-Mezard P;Saunier S
纤毛病是一大类由初级纤毛缺陷引起的临床和遗传异质性疾病。在这里，我们在来自 5 个肾病 (NPH) 和视网膜变性（纤毛病的两种最常见表现）家族的 8 名患者中发现了 TRAF3IP1（TNF 受体相关因子相互作用蛋白 1）突变。 TRAF3IP1 编码 IFT54，这是纤毛发生所需的 IFT-B 复合物的一个亚基。已发现的突变会导致患者出现轻度纤毛缺陷，但也揭示了 IFT54 通过 MAP4（微管相关蛋白 4）作为微管稳定性负调节因子的意想不到的作用。微管缺陷与肾细胞上皮化/极性的改变以及斑马鱼胚胎中的前肾囊肿和小眼症有关。我们的研究结果强调了细胞质微管动力学的调节是 IFT54 蛋白在纤毛之外的作用，有助于 NPH 相关纤毛病的发展。 肾痈（NPH）是纤毛病的常见表现。在这里，作者鉴定了 NPH 患者鞭毛内转运 54 (IFT54) 的突变，并发现 IFT54 在调节细胞质微管动力学中的纤毛外作用，这有助于该疾病的病理生理学。
Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies. Nephrophthisis (NPH) is a common manifestation of ciliopathy diseases. Here the authors identify mutations in intraflagellar transport 54 (IFT54) in patients with NPH and discover an extra-ciliary role for IFT54 in regulating cytoplasmic microtubule dynamics, that contributes to the pathophysiology of this disease.