Promising new therapeutic targets for regulation of inflammation and immunity: RING-type E3 ubiquitin ligases

Abstract

© 2018 European Federation of Immunological Societies Ubiquitin–proteasome system (UPS) is a primary signaling pathway for regulation of protein turnover and removal of misfolded proteins in eukaryotic cells. Enzymes of the UPS pathway - E1 activating, E2 conjugating, E3 ligating - act together to covalently tag substrate proteins with a chain of ubiquitins, small regulatory proteins. The poly-ubiquitin chain then serves as a recognition motif for 26S proteasome to recognize and degrade the substrate. In recent years UPS has emerged as attractive enzymatic cascade for development of novel therapeutics against various human diseases. Building on the previous success of targeting this pathway in cancer – the broader scientific community is currently looking for ways to elucidate functions of E3 ligases, substrate-specific members of the UPS. RING-type E3 ubiquitin ligases, the largest class of E3s, represent prospective targets for small molecule modulation and their importance is reinforced by ever growing evidence of playing role in non-cancer diseases, primarily associated with inflammatory and immune disorders. In this review, we aim to briefly cover the current knowledge of biological functions of RING-type E3 ligases in inflammation and immunity.