线性泛素链修饰是一种新型的蛋白质泛素化修饰，在先天免疫、炎症和选择性细胞自噬等相关的信号通路中扮演着重要的角色。线性泛素链组装复合物LUBAC是目前发现的唯一一个介导线性泛素化修饰的E3酶复合物，由催化亚基HOIP和两个调节亚基Sharpin和HOIL-1L组成。LUBAC蛋白的功能异常或缺失在小鼠和人类身上会引起免疫缺陷、慢性炎症等症状。虽然近年来针对LUBAC和线性泛素链化修饰的研究取得了长足的进展，但是仍有很多重要的基本科学问题没有被解决。本申请课题将综合采用结构生物学、化学生物学、细胞生物学等多学科方法来研究和阐明LUBAC的组装和调控机理，寻找被线性泛素化修饰的相关未知底物以及揭示相关底物被线性泛素化修饰的分子机制。同时，研究和阐明相关毒素蛋白作用于LUBAC的分子机制，并研发活性小分子来干扰相关毒素蛋白与LUBAC之间的相互作用，用于后续潜在的疾病治疗研究。

Linear ubiquitination, a novel type of protein ubiquitination modification, plays crucial roles in numerous signaling pathways related to innate immune, inflammation and selective autophagy. The linear ubiquitin chain assembly complex, LUBAC, which consists of a catalytic subunit HOIP and two regulatory subunits, Sharpin and HOIL-1L, is the only currently known E3 ubiquitin ligase complex that catalyzes the formation of linear ubiquitin chain. The dysfunction or deficiency of LUBAC components leads to severe immune system disorders and chronic inflammation in mouse or in human. The recent explosion of interests in LUBAC and the linear ubiquitination has prompted tremendous progresses in this field. However, there are still many important fundamental questions related to LUBAC and the linear ubiquitination needed to be addressed. In this research proposal, using multidisciplinary approaches including structure biology, chemical biology and cell biology methods, we seek to uncover the molecular mechanism underlying the assembly and regulation of LUBAC as well as the linear ubiquitination of relevant substrates by LUBAC, and to find unknown relevant substrate modified by LUBAC-mediated linear ubiquitination. Meanwhile, we also plan to elucidate the interaction mechanisms between some toxins and LUBAC, thereby to develop small molecule antagonists to interfere the interactions between some toxins and LUBAC for the potential medical treatments of some relevant diseases.