胆固醇调控细胞ACE2重分布的分子机制研究

作为新冠病毒的受体，ACE2的研究理应得到极大的重视，目前对其介导病毒入侵机制的探索已逐渐达成共识，但对其在细胞内的转运和分布特点则鲜有报道。一般而言，细胞膜表面受体的表达和分布存在一个“分泌-循环-降解”的动态平衡，我们前期的研究发现胆固醇可以打破这一动态平衡，促进ACE2在细胞膜表面的重分布，对其机制的探究过程中，我们发现细胞内存在一个转运相关蛋白GP73，在胆固醇调控ACE2重分布的过程中扮演着不可或缺的角色。更重要的是，GP73既可以通过其胆固醇结合区域感应胆固醇，又与ACE2存在直接的蛋白间相互作用，提示它可能是胆固醇调控ACE2重分布的“桥梁”。在此基础上，本课题将进一步研究胆固醇影响ACE2重分布这一现象的特点和规律，阐明GP73作为“桥梁”调控此现象的分子机制，丰富和更新胆固醇感应器蛋白库的同时，为新冠病毒的预防和治疗提供新的靶点，助力疫情防控。

As the receptor of 2019-nCoV, there are few reports on the cellular trafficking and distribution of ACE2, even though the mechanism of ACE2-mediated virus invasion had been clarified gradually. Generally, cell surface ACE2 exists in a "secretion-recycling-degradation" dynamic balance as other receptors, our previous results found that cholesterol could break the dynamic balance of ACE2, upregulating its cell surface amounts. As for mechnism, we found a transport-associated protein—GP73, which plays an indispensable role on the cholesterol-mediated redistribution of ACE2. On the one hand, GP73 could sense cholesterol with its cholesterol-binding motif; on the other hand, GP73 could interact with ACE2 directly. On this basis, we would further investigate the characteristics of cholesterol affecting ACE2 redistribution, clarifying the molecular mechanism of GP73 regluating the phenomenon as a bridge. This study is expected to update cholesterol sensor library and provide new therapeutic targets for the treatment of 2019-nCoV.