Mechanism of MALT1 Regulation by a Novel Ubiquitin Ligase

 描述(由申请人提供)：E3泛素连接酶因其主要的生物学作用和靶点特异性而成为癌症的有吸引力的治疗靶点，然而它们在自身免疫性疾病的治疗方面的应用仍处于发展阶段。最近，我们发现一种新的泛素E3连接酶HECTD3相互作用并泛素化MALT1，MALT1是免疫细胞中转录因子NF-kB的关键正向调节因子，对淋巴瘤细胞的存活起重要作用，并在多发性硬化症(一种与中枢神经系统脱髓鞘相关的慢性炎症性疾病)中发挥重要作用。HECTD3介导的MALT1泛素化导致MALT1的稳定，促进顺铂诱导的癌细胞存活，在实验性自身免疫性脑脊髓炎(EAE)这一人类多发性硬化小鼠模型中起着关键作用。我们还发现HECTD3基因敲除小鼠降低了EAE的严重程度，减少了Th17细胞因子的产生，降低了MALT1及其泛素化水平，减少了Th17细胞对中枢神经系统的渗透，表明HECTD3通过MALT1调控EAE中的Th17反应。尽管HECTD3在这些疾病中很重要，但人们对HECTD3的结构及其在MALT1中的作用机制知之甚少。因此，这项建议的主要目标是破译HECTD3在MALT1调控中的机制。具体地说，我们建议使用体外、体内和结构方法来研究HECTD3对MALT1修饰的分子机制。拟议的研究将导致对MALT1泛素化和HECTD3调节的详细分子见解，以及HECTD3-MALT1相互作用的细节。最终，这项研究产生的数据将成为开发针对淋巴瘤、多发性硬化症和乳腺癌的更具体、更有效的免疫疗法的起点，鉴于目前的治疗挑战和治疗选择的减少，这一点非常重要。

 DESCRIPTION (provided by applicant): E3 Ubiquitin ligases have been attractive therapeutic targets in cancer, due to their major biological roles, and target specificity, however their use i development of therapies for autoimmune disorders remains in infancy. Recently, we found that a novel ubiquitin E3 ligase HECTD3 interacts and ubiquitinates MALT1, which is a critical positive regulator of the transcription factor NF-kB in immune cells and strongly contributes to cell survival in lymphomas and plays an essential role in multiple sclerosis, a chronic inflammatory disease associated with demyelination of central nervous system. The MALT1 ubiquitination mediated by HECTD3 leads to MALT1 stabilization, and promotes cancer cell survival of cisplatin-induced apoptosis, and plays a critical role in Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for multiple sclerosis in humans. We also found that HECTD3 knock-out mice have reduced EAE severity, diminished Th17 cytokine production, lower levels of MALT1 and its ubiquitination, and reduced infiltration of Th17 cells into the central nervous system, suggesting that HECTD3 controls the Th17 response in EAE through MALT1 regulation. Despite the importance of HECTD3 in these diseases, very little is known about the structure of HECTD3 and its mechanism of action on MALT1. Thus, the major goal of this proposal is to decipher the mechanisms of HECTD3 in MALT1 regulation. Specifically, we propose to investigate the molecular mechanisms by which HECTD3 contributes to MALT1 modifications using in vitro, in vivo, and structural approaches. The proposed studies will result in detailed molecular insights into MALT1 ubiquitination and regulation by HECTD3, as well as details on the HECTD3-MALT1 interactions. Ultimately, data generated by this study will serve as a starting point for development of more specific and more effective immune therapies against lymphomas, multiple sclerosis, and breast cancer, which is of major importance, given the current treatment challenges and the reduced therapeutic options.