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.
This project is clinically relevant to multiple sclerosis therapy because the HECTD3 E3 ubiquitin ligase is found to control the severity of the experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis mouse model. We found that loss of Hectd3 reduced EAE severity. The proposed study will elucidate the structure and activity of HECTD3 and its interaction with MALT1. This is particularly significant in the clinic because the current studies will open avenues for development of more specific and more effective immune therapies for multiple sclerosis, given the current treatment challenges and the reduced therapeutic options.
