纤毛病蛋白HYLS1调控纤毛发生的分子机理

HYLS1 (Hydrolethalus Syndrome 1) gene mutation leads to a severe perinatal lethal disorder termed hydrolethalus syndrome (HLS), a severe fetal malformation syndrome. It has been reported that HYLS1 localizes to centrioles, and play roles in ciliogenesis but not in centriole duplication, suggesting that HLS disease is caused by defects in cilia function. But the molecular mechanism on how HYLS1 regulates cilia formation remains to be understood. The applicant has long experience in studying ciliogenesis using C.elegans as a model organism, has published several cilia related papers on high impact journals such as Nature Cell Biology, Nature Communications, Current Opinion in Cell Biology and Journal of Cell Biology et al. In this application, in order to understand the molecular mechanism HYLS1 played on cilia formation, we will use C.elegans model organism to detailed characterization of the ciliary phenotype caused by HYLS1 deletion. In addition, we will test if the mechanism is also conserved in mammals. Our proposed studies will shed light on our understating of the function of HYLS1 protein, the mechanism of ciliogenesis and the pathogenesis of HLS disease.

HYLS1 (Hydrolethalus Syndrome 1) 基因突变导致围生期致死性胎儿畸形综合症Hydrolethalus Syndrome (HLS)。已报道HYLS1定位于中心粒，但不影响中心粒的复制，而是特异性的调控纤毛发生，表明HLS疾病是由于纤毛功能异常所致。但HYLS1调控纤毛形成的分子机制仍不清楚。申请人长期从事模式生物秀丽隐杆线虫纤毛发生的机制研究，在Nature Cell Biology, Nature Communications等杂志发表了多篇纤毛研究文章。本项目拟利用秀丽隐杆线虫为模式，对线虫HYLS1同源基因hyls-1缺失突变体的纤毛缺陷表型进行系统详细的分析，以期确定HYLS1调控纤毛形成的主要因素及分子机理，并在哺乳动物细胞中验证机理保守性。项目对深入理解HYLS1的生物学功能，纤毛发生机制，HLS综合症致病机理等具有重要意义。

HYLS1作为一个中心粒蛋白，其突变导致纤毛病Hydrolethalus syndrome。本项目以模式生物秀丽隐杆线虫为模式，详细研究了HYLS1调控纤毛发生的分子机制，证明了HYLS1主要通过调控纤毛过渡纤维蛋白FBF1的定位而调控纤毛发生，并发现纤毛病蛋白TALPID3和ANKRD26作用于HYLS1的下游共同调控FBF1的定位，并进一步发现该通路在哺乳动物中也是保守的 (Nature Communications 2020, 11(1):2196)。另外，我们通过对果蝇中HYLS1功能的研究，发现HYLS1在中心粒的组装中也发挥着及其重要的作用 (Frontier in Cell Developmental Biology 2020, 8:301), 为将来进一步研究HYLS1的功能指明了方向、奠定了基础。项目基本按原计划执行，研究目标顺利完成，共发表了4篇SCI论文。