xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and RCK kinase cascade to regulate cilia morphology.
xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and RCK kinase cascade to regulate cilia morphology.
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DOI：
10.1016/j.cub.2021.10.027
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发表时间：
2021-12-20
期刊：
影响因子：
--
通讯作者：
Sengupta P
中科院分区：
文献类型：
--
作者：
Maurya AK;Sengupta P
初级纤毛是基于微管（MT）的细胞器，其在多种细胞类型中介导感觉功能。纤毛结构或功能的破坏导致称为纤毛病的多种疾病。高度保守的CCRK和RCK激酶（ICK/MOK/MAK）负调控衣原体纤毛的长度和结构。线虫和哺乳动物细胞。这种激酶级联的活性如何被调节以精确地调节纤毛结构尚不清楚。最近已显示含有蛋白质FAM 149 B1的未知功能结构域DUF 3719的突变通过未知机制延长纤毛并导致纤毛病Joubert综合征。在这里，我们确定了XBX-4，一种与人FAM 149 B1相关的含DUF 3719的蛋白，作为C.优雅的。如在dyf-18和dyf-5突变体中，感觉神经元纤毛在xbx-4突变体中伸长，并表现出稳定的轴丝MT。XBX-4通过促进DYF-18 CCRK的功能来调节DYF-5 MAK的定位和功能。我们发现，Joubert综合征相关的突变在XBX-4 DUF 3719域也延长纤毛在C。优雅的。我们的研究结果确定了这种高度保守的激酶途径的一种新的后生动物特异性调节剂，并表明FAM 149 B1可能通过CCRK/RCK激酶途径类似地调节人类的纤毛稳态。Maurya和Sengupta的研究表明，C.秀丽线虫XBX-4 DUF 3719蛋白在CCRK/RCK级联的上游起作用以调节感觉纤毛结构。人DUF 3719蛋白FAM 149 B1以及XBX-4延长纤毛中的Joubert综合征相关突变这种激酶级联的背景特异性调节可以精确调节纤毛结构。
Primary cilia are microtubule (MT)-based organelles that mediate sensory functions in multiple cell types. Disruption of cilia structure or function leads to a diverse collection of diseases termed ciliopathies. The highly conserved CCRK and RCK kinases (ICK/MOK/MAK) negatively regulate cilia length and structure in Chlamydomonas, C. elegans, and mammalian cells. How the activity of this kinase cascade is tuned to precisely regulate cilia architecture is unclear. Mutations in the Domain of Unknown Function DUF3719-containing protein FAM149B1 have recently been shown to elongate cilia via unknown mechanisms and result in the ciliopathy Joubert syndrome. Here we identify XBX-4, a DUF3719-containing protein related to human FAM149B1, as a regulator of the DYF-18 CCRK and DYF-5 MAK kinase pathway in C. elegans. As in dyf-18 and dyf-5 mutants, sensory neuron cilia are elongated in xbx-4 mutants and exhibit stabilized axonemal MTs. XBX-4 promotes DYF-18 CCRK function to regulate localization and function of DYF-5 MAK. We find that Joubert syndrome-associated mutations in the XBX-4 DUF3719 domain also elongate cilia in C. elegans. Our results identify a new metazoan-specific regulator of this highly conserved kinase pathway, and suggest that FAM149B1 may similarly act via the CCRK/RCK kinase pathway to regulate ciliary homeostasis in humans. Maurya and Sengupta show that the C. elegans XBX-4 DUF3719 protein acts upstream of the CCRK/RCK cascade to regulate sensory cilia structure. Joubert syndrome-associated mutations in the human DUF3719 protein FAM149B1 as well as XBX-4 elongate cilia. Context-specific tuning of this kinase cascade may allow precise modulation of cilia architecture.
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