WDR91-WDR81复合体调控内吞体-溶酶体运输及神经发育

WDR91-WDR81 complex-dependent endolysosomal trafficking and neural development

WD40重复序列蛋白在真核生物中广泛存在,并参与胞内运输、信号转导、凋亡发生、转录调控等生命过程.通过以秀丽隐杆线虫(Caenorhabditis elegans)为模式动物进行遗传筛选,本课题组发现了两个新基因,其人类同源基因编码WD40重复序列蛋白WDR91和WDR81,然而此前对这两种蛋白的功能知之甚少.本课题组后续工作发现, WDR91和WDR81形成复合体,作为晚期内吞体的特征性小GTP酶Rab7的效应因子被招募到内吞体上,与Ⅲ型磷酯酰肌醇-3-激酶(PI3K)复合体的Beclin 1亚基相互作用,抑制内吞体上磷脂酰肌醇3-磷酸(PtdIns3P)的合成,使早期内吞体向晚期内吞体转化,从而确保内吞体-溶酶体运输得以实现. WDR91-WDR81复合体与神经发育紧密相关,具体表现在特异性敲除WDR91的小鼠神经突起生长受损,而WDR81通过内吞体SARA-TGFβ信号通路影响成体神经发生.此外, WDR81还可作为衔接蛋白结合p62和LC3C,以不依赖于WDR91-WDR81复合体的形式促进蛋白聚集体的选择性自噬.这些发现为揭示WDR91和WDR81相关的神经系统疾病致病机制提供了重要理论依据.

WD40-repeat proteins participate in diverse cellular processes, such as intracellular trafficking, signal transduction, apoptosis, and transcriptional regulation. From genetic screens of the model organism Caenorhabditis elegans, we identified two novel genes that encode homologs of mammalian WDR91 and WDR81, two WD40-repeat proteins with previously unknown functions. Our study revealed that WDR91 and WDR81 form a complex that functions as an effector of the late endosome-specific Rab GTPase Rab7. The WDR91-WDR81 complex is recruited to the endosomes, where these proteins interact with Beclin 1, a subunit of class III PI3K complex, thereby inhibiting the endosomal synthesis of early endosome-specific PtdIns3P and allowing the conversion of early endosomes to late endosomes, ensuring the delivery of the endosomal cargos to the lysosomes. WDR91 or WDR81 loss impairs neurogenesis and development, possibly by affecting endosome-dependent signaling. Furthermore, WDR81 plays a critical role in aggrephagy by interacting with p62 and LC3C, distinct from its role in endosomal trafficking. Taken together, these findings provide important mechanistic insights into WDR91- and WDR81-related neurodevelopmental disorders.