HECT, UBA and WWE domain containing 1 (HUWE1) (HUWE1)

HECT, UBA and WWE domain containing 1 (HUWE1) is a large E3 ubiquitin-protein ligase belonging to the HECT family, which plays a central role in maintaining cellular protein homeostasis (UniProt Q7Z6Z7). It functions by tagging specific substrate proteins with ubiquitin chains, marking them for degradation by the 26S proteasome. HUWE1 is involved in a wide array of biological processes, including the DNA damage response, cell cycle regulation, and apoptosis, by targeting key proteins such as the anti-apoptotic factor MCL1, the oncoprotein MYC, and the tumor suppressor p53 (PMID: 15958491, 28218735). Due to its ability to regulate both oncogenic and tumor-suppressive pathways, its role in cancer is highly context-dependent and varies across different tissue types. Beyond its implications in oncology, mutations in the HUWE1 gene are a known cause of X-linked intellectual disability and other neurodevelopmental disorders (PMID: 27535533). In the realm of drug development, HUWE1 is being investigated as a target for small-molecule inhibitors and as a recruited ligase for targeted protein degradation via molecular glues like BI-3802 (PMID: 32555461). However, the broad spectrum of its cellular targets presents significant challenges regarding therapeutic specificity and potential systemic toxicity.

Other names

ARF-BP1MULELASU1UREB1HECTH9E3 ubiquitin-protein ligase HUWE1Large structure of UREB1

Targeted protein degradation via recruitment of the HUWE1 E3 ligase to specific substrates (e.g., BCL6) or direct inhibition of the HECT domain catalytic activity to stabilize tumor suppressors (PMID: 32555461, 28218735).