Mechanism of MALT1 Regulation by a Novel Ubiquitin Ligase

新型泛素连接酶调节 MALT1 的机制

基本信息

批准号：
8821943
负责人：
HONGMIN LI
金额：
$ 22.74万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-13 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8821943
关键词：
Apoptosis Autoimmune Diseases Autoimmune Responses Binding Biological Biological Assay Cell Survival Cells Chronic Cisplatin Clinic Complex Data Demyelinations Development Disease Drug Design Drug Targeting Ensure Experimental Autoimmune Encephalomyelitis Goals Human Immune Immune response Immune system Immunotherapy In Vitro Infiltration Inflammatory Interleukin-17 Investigation Knockout Mice Laboratories Length Lymphoma Lysine Malignant Neoplasms Mass Spectrum Analysis Mediating Modification Molecular Multiple Sclerosis Mutagenesis NF-kappa B Neuraxis Pathway interactions Play Post-Translational Protein Processing Production Proteins Protocols documentation Regulation Research Role Severities Signal Transduction Site Specificity Structure T-Lymphocyte Tertiary Protein Structure Therapeutic Ubiquitin Ubiquitination Work X-Ray Crystallography base cancer cell cancer therapy clinically relevant cytokine high reward human disease in vivo infancy innovation insight knock-down malignant breast neoplasm mouse model mutant neoplastic cell novel public health relevance research study response therapeutic target therapy development ubiquitin ligase ubiquitin-protein ligase

项目摘要

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.

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点特异性而成为癌症中有吸引力的治疗靶点，但它们在自身免疫性疾病疗法开发中的应用仍处于起步阶段。泛素 E3 连接酶 HECTD3 与 MALT1 相互作用并泛素化，MALT1 是免疫细胞中转录因子 NF-kB 的关键正调节因子，对细胞存活有重要作用HECTD3 介导的 MALT1 泛素化导致 MALT1 稳定，促进顺铂诱导的细胞凋亡的癌细胞存活，并在多发性硬化症中发挥重要作用。在实验性自身免疫性脑脊髓炎（EAE）（一种人类多发性硬化症小鼠模型）中，我们还发现 HECTD3 敲除小鼠具有。 EAE 严重程度降低，Th17 细胞因子产生减少，MALT1 及其泛素化水平降低，Th17 细胞向中枢神经系统的浸润减少，表明 HECTD3 通过 MALT1 调节控制 EAE 中的 Th17 反应，尽管 HECTD3 在这些疾病中很重要。对于 HECTD3 的结构及其对 MALT1 的作用机制知之甚少，因此，该提案的主要目标是破译 HECTD3 的机制。具体来说，我们建议使用体外、体内和结构方法研究 HECTD3 促进 MALT1 修饰的分子机制。拟议的研究将获得对 HECTD3 泛素化和调节的详细分子见解。以及 HECTD3-MALT1 相互作用的详细信息最终，这项研究产生的数据将作为开发针对淋巴瘤、多发性硬化症、更具体和更有效的免疫疗法的起点。考虑到当前的治疗挑战和治疗选择的减少，乳腺癌至关重要。