Exploring the "Other" subfamily of HECT E3-ligases for therapeutic intervention

The HECT E3 ligase family regulates key cellular signaling pathways, with its 28 members divided into three sub-families: NEDD4 subfamily (9 members), HERC subfamily (6 members) and "Other" subfamily (13 members). Here, we focus on the less-explored "Other" subfamily and discuss the recent findings pertaining to their biolog-ical roles. The N-terminal regions preceding the conserved HECT domains are significantly diverse in length and sequence composition, and are mostly unstructured, except for short regions that incorporate known substrate-binding domains. In some of the better-characterized "Other" members (e.g., HUWE1, AREL1 and UBE3C), structure analysis shows that the extended region (similar to aa 50) adjacent to the HECT domain affects the sta-bility and activity of the protein. The enzymatic activity is also influenced by interactions with different adaptor proteins and inter/intramolecular interactions. Primarily, the "Other" subfamily members assemble atypical ubiquitin linkages, with some cooperating with E3 ligases from the other subfamilies to form branched ubiquitin chains on substrates. Viruses and pathogenic bacteria target and hijack the activities of "Other" subfamily mem-bers to evade host immune responses and cause diseases. As such, these HECT E3 ligases have emerged as poten-tial candidates for therapeutic drug development. (C) 2021 Elsevier Inc. All rights reserved.