Decoding the Molecular Mechanisms of SUMO and Ubiquitin Pathways: From E3 Ligases to proteases

This proposal aims to investigate the molecular mechanisms underlying post-translational modification of proteins by SUMO and ubiquitin. SUMOylation and ubiquitination are tightly regulated cellular processes, primarily governed by a dynamic equilibrium between conjugation by specific E3 ligases and deconjugation by deubiquitinases (DUBs) and/or deSUMOylases (SENPs). These enzymes respectively add and remove SUMO/ubiquitin, thereby regulating protein function.

Our focus will be on: large E3 ligases,  investigating the mechanisms of SUMO conjugation mediated by the Smc5/6 complex; human proteases, characterizing the poorly understood human SENP3 and SENP5; viral and bacterial proteases, identifying and characterizing novel CE-clan proteases from infectious agents that target the host SUMO/ubiquitin pathway to facilitate infection.

Human Antimicrobial RNases (hRNases) involved in the host innate immune system are promising templates for drug design. Our laboratory has a long-standing experience in the structure-function analysis of human RNases belonging to the vertebrate-specific RNaseA superfamily [1-4]. Our results highlighted the multifaceted role of antimicrobial RNases, where catalytic-dependent and -independent activities complement each other by a double-sword mechanism [3,4]. Currently, we are focusing on the eosinophil derived neurotoxin (EDN or RNase2) that is secreted during viral infection. Human RNase2 evolved from a common ancestor within primate divergence and is unique for Old World monkeys and hominoids [5], offering an ideal working model for immunology research. Ongoing structure-function studies in our laboratory have enabled us to identify the main structural determinants for some of its antiviral and immunomodulatory activities.

Here, we plan to pursue our project to unravel the structural determinants for human RNase2 unique properties and assist the development of innovative tailored drugs to treat viral infection.