Mechanism of MALT1 Regulation by a Novel Ubiquitin Ligase

 描述（由申请人提供）：E3泛素连接酶由于其主要的生物学作用和靶特异性而成为癌症中有吸引力的治疗靶标，然而其在开发自身免疫性疾病的疗法中的用途仍处于婴儿期。最近，我们发现一种新的泛素E3连接酶HECTD 3相互作用并泛素化MALT 1，MALT 1是免疫细胞中转录因子NF-kB的关键正调节因子，对淋巴瘤中的细胞存活有很大贡献，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）中起重要作用。由HECTD 3介导的MALT 1泛素化导致MALT 1稳定，并促进顺铂诱导的细胞凋亡的癌细胞存活，并且在实验性自身免疫性脑脊髓炎（EAE）（人类多发性硬化症的小鼠模型）中起关键作用。我们还发现，HECTD 3基因敲除小鼠EAE严重程度降低，Th 17细胞因子产生减少，MALT 1及其泛素化水平降低，Th 17细胞向中枢神经系统的浸润减少，表明HECTD 3通过MALT 1调节控制EAE中的Th 17反应。尽管HECTD 3在这些疾病中的重要性，但对HECTD 3的结构及其对MALT 1的作用机制知之甚少。因此，该提案的主要目标是破译HECTD 3在MALT 1调节中的机制。具体来说，我们建议调查的分子机制，HECTD 3有助于MALT 1修改使用在体外，体内和结构的方法。拟议的研究将导致对MALT 1泛素化和HECTD 3调控的详细分子见解，以及HECTD 3-MALT 1相互作用的细节。最终，本研究产生的数据将作为开发针对淋巴瘤、多发性硬化症和乳腺癌的更特异、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减少，这一点至关重要。

 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.