RNA结合蛋白NOC4L调控NK细胞发育的机制研究

Natural killer (NK) cells are important innate immune cells，and they are responsible for immune surveillance of abnormal cells. NK cell development is a sequential process regulated by multiple receptors, signaling molecules and transcription factors. Current studies on NK cell development mostly focus on these genes encoding functional proteins. Despite this, post-transcriptional regulation of NK cell development is rarely reported. Although RNA-binding proteins (RBPs) play important roles in many biological processes. Whether these proteins are required for NK cell generation remains elusive. Based on bioinformatics analysis, the applicant preliminarily showed that NOC4L exhibited a tendency of gradual decline along NK cell maturation so that we made a mouse model in which NOC4L gene was floxed. We initially observed that NK cell-specific deletion of NOC4L led to a severe defect in NK cell development, suggesting that NOC4L protein may be indispensable for NK cell development. On the basis of these data, we are planning to further study the molecular mechanism underlying NOC4L regulation of NK cell development. We hypothesize that NOC4L protein monitors NK cell development probably by stabilizing those critical RNAs, which encode the essential proteins related with NK cell development (such as cytokine receptors, signaling molecules as well as transcription factors). The current study will reveal a novel pathway post-transcriptionally regulating NK cell development.

自然杀伤（NK）细胞是重要的固有免疫细胞，负责免疫监视体内异常细胞。NK细胞发育是一个渐进的过程，受到受体、信号转导分子和转录因子的严密调控，目前NK细胞发育调控研究主要侧重于分析这些功能基因编码蛋白。RNA结合蛋白（RBPs）主要参与转录后调控，其在很多生物过程中起重要作用。RBPs参与的转录后调控是否影响NK细胞发育，目前还不清楚。申请人通过生物信息学大数据研究NK细胞RBPs的表达特点，发现NOC4L的表达在NK细胞发育过程中逐渐降低。进而制备了条件性NOC4L敲除小鼠，初步观察到NOC4L缺失严重影响NK细胞发育。基于上述的初步的研究发现，我们拟研究NOC4L蛋白调控NK细胞发育的分子机制。我们推测该蛋白可能通过调控参与编码NK细胞发育关键蛋白的RNA稳定性。该研究将会揭示一种全新的NK细胞发育调控方式。