p62/SQSTM1在巨噬细胞对白念珠菌泛素化识别及吞噬的作用与机制研究

巨噬细胞的吞噬作用是控制白念珠菌感染的重要途径。p62/SQSTM1是一种多功能泛素化结合蛋白，可识别多种泛素化细菌并促进降解。前期工作发现白念珠菌可导致巨噬细胞p62蛋白水平明显升高，并诱导p62 Ser403位点磷酸化（此位点主要参与泛素化识别）；干扰p62表达后巨噬细胞对白念珠菌的吞噬能力减弱；p62髓系细胞选择性敲除小鼠白念珠菌系统感染的存活时间缩短。因此提出假说：巨噬细胞p62蛋白水平升高可能通过识别泛素化的白念珠菌，促进细胞膜表面吞噬识别受体的活化，增强对白念珠菌的吞噬与清除。本研究拟探索白念珠菌感染诱导p62上调的原因，使用p62髓系细胞选择性敲除小鼠，验证p62在抗白念珠菌系统感染过程中发挥的免疫效应，探索p62能否识别泛素化的白念珠菌，并挖掘p62促进吞噬水平的机制。通过研究p62在抗白念珠菌感染中所发挥的作用，有望将p62作为白念珠菌系统感染的临床评估及治疗靶点。

The phagocytosis function is an important way to control Candida albicans infection in macrophages. p62/SQSTM1 is a multifunctional ubiquitinated binding protein that can recognize a variety of ubiquitinated bacteria and promote degradation. Preliminary work have found that C. albicans induce the increased protein level of p62, and induce the phosphorylation of Ser403 in p62 (this site is involved in ubiquitin recognition). Knock down p62 expression reduced the phagocytosis rate. The survival time of p62 myeloid selective knockout mice with C. albicans systemic infection is shortened. Therefore, we hypothesized that the increased level of macrophage p62 protein may recognize the ubiquitinated C. albicans, promote the activation of the phagocytic recognition receptor on the cell membrane surface, and strengthen the phagocytosis and clearance against C. albicans. We will explore the reasons for the up-regulation of p62 induced by C. albicans infection. By using p62 myeloid selective knock out mice, we will verify the immune effect of p62 in the process of anti-C. albicans infection, explore whether p62 can recognize ubiquitinated C. albicans, and explore the mechanism of increased level of phagocytosis induced by p62. By studying the role of p62 in preventing C. albicans infection, it is expected that p62 can be used as the clinical evaluation and treatment target for systemic C. albicans infection.