NudCL2在细胞自噬介导的纤毛形成过程中的作用及机制

细胞纤毛是以微管为基础、突出于细胞表面的特化细胞器，在胚胎发育及成体组织稳态中具重要作用，其异常与多种人类疾病相关。自噬是细胞内溶酶体介导的降解过程，也在上述过程中扮演重要角色。最新研究表明，自噬可参与纤毛形成过程，但具体机制未明。我们长期致力于细胞核分布基因C（NudC）家族研究。最近发现，下调NudC家族成员NudCL2（NudC-like protein 2）可致细胞纤毛变短及数量减少。在斑马鱼中，敲低NudCL2不仅导致胚胎Kuppfer’s Vesicle内纤毛变短，也造成内脏器官转位等纤毛异常表型。进一步研究显示，NudCL2不仅参与细胞自噬的调控，而且还与自噬重要调节蛋白LC3互作，调节其蛋白稳定性。由此，我们认为“NudCL2可能通过自噬调节细胞纤毛生长，进而影响动物胚胎发育过程”。本项目拟探讨NudCL2在自噬及其介导的纤毛生长中的调节作用及机制，为纤毛异常疾病诊治提供。

Cilia are evolutionarily conserved microtubule-based organelles that project from the cell surface which play important roles in embryonic development and adult tissue homeostasis. Defects in cilia assembly and function are associated with a range of human diseases. Autophagy is a catabolic process by which the damaged components of the cell are degraded by autolysosomes, and it also contributes to embryonic development and adult tissue homeostasis. Although, the interplay between autophagy and ciliogenesis has been suggested, the role of autophagy in ciliogenesis is largely unknown. We focus on the biological functions of nuclear distribution gene C (NudC) family for many years. Recently, we found that knockdown of NudCL2 results in the decrease of the length and the number of primary cilia in MEF cells. Moreover, we found that deletion of NudCL2 in zebrafish embryos not only decreases the length of the KV cilia, but also causes the defects in left-right asymmetry. Further data showed that down-regulation of NudCL2 reduces autophagic activity. Moreover, we found that NudCL2 interacts with LC3, a key autophagy regulator. Depletion of NudCL2 causes the decrease in LC3 protein level. Thus, we propose that NudCL2 may involve in ciliogenesis by regulating autophagy, and play important role in embryonic development. In this proposal, we will systematically characterize the role of NudCL2 in ciliogenesis via autophagy, and elucidate its possible molecular mechanism, which may provide novel potential therapeutic targets for the human diseases related to the dysfunction of cilia.