The giant E3 ligase HUWE1 is linked to tumorigenesis, spermatogenesis, intellectual disability, and inflammatory diseases

Abstract

E3 ubiquitin ligases determine the substrate specificity and catalyze the ubiquitination of lysine residues. HUWE1 is a catalytic HECT domain-containing giant E3 ligase that contains a substrate-binding ring structure, and mediates the ubiquitination of more than 40 diverse substrates. HUWE1 serves as a central node in cellular stress responses, cell growth and death, signal transduction, etc. The expanding atlas of HUWE1 substrates presents a major challenge for the potential therapeutic application of HUWE1 in a particular disease. In addition, HUWE1 has been demonstrated to play contradictory roles in certain aspects of tumor progression in either an oncogenic or a tumor-suppressive manner. We recently defined novel roles of HUWE1 in promoting the activation of multiple inflammasomes. Inflammasome activation-mediated immune responses might lead to multifunctional effects on tumor therapy, inflammation, and autoimmune diseases. In this review, we summarize the known substrates and pleiotropic functions of HUWE1 in different types of cells and models, including its involvement in development, cancer, neuronal disorder and infectious disease. We also discuss the advances in cryo-EM-structural analysis for a functional-mechanistic understanding of HUWE1 in modulating the multitudinous diverse substrates, and introduce the possibility of revisiting the comprehensive roles of HUWE1 in multiple aspects within one microenvironment, which will shed light on the potential therapeutic application of targeting giant E3 ligases like HUWE1.

HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways

“…HUWE1 has been reported to regulate a diverse and growing number of cellular pathways through the targeted degradation of structurally diverse proteins (Giles and Grill, 2020; Qi et al, 2022). In order to characterize the mechanisms HUWE1 utilizes to enable such plasticity towards its substrates, we performed quantitative and deep whole cell proteomics to identify proteins whose steady-state abundance is elevated upon HUWE1 loss of function.…”

“…HUWE1 is an enigmatic ubiquitin ligase that has been implicated to regulate numerous cellular pathways including DNA repair, transcription, proliferation, apoptosis, and cell signaling (Qi et al, 2022). Further, HUWE1 has been described to both promote and restrict tumorigenesis, as well as play critical roles in neurodevelopmental pathways (Adhikary et al, 2005; Forget et al, 2014; Giles and Grill, 2020; Gong et al, 2020; Hao et al, 2012; Inoue et al, 2013; King et al, 2016; Kunz et al, 2020; Myant et al, 2017; Opperman et al, 2017; Peter et al, 2014; Yang et al, 2018; Zhao et al, 2009; Zhao et al, 2008).…”

“…Substrate ubiquitylation is often tightly regulated to prevent spurious targeting of critical substrates and ensure precise pathway regulation. Some ligases reportedly engage a highly diverse set of substrates with undefined mechanisms (Brunet et al, 2020; Kim et al, 2021; Qi et al, 2022; Wang et al, 2020). How these broadly acting ligases engage their substrates, and how these ligases are regulated remain open questions.…”

“…HUWE1 is one such enigmatic ubiquitin ligase that has many reported substrates regulating highly diverse cellular pathways (Giles and Grill, 2020; Qi et al, 2022). HUWE1 is a giant and highly abundant HECT-domain ubiquitin ligase with a variety of protein interaction domains that have been shown to target specific substrates (Adhikary et al, 2005; Chen et al, 2005; Liu et al, 2005; Zhong et al, 2005).…”

The E3 Ligases in Cervical Cancer and Endometrial Cancer

“…The number of substrates that can be ubiquitinated by HUWEI1 has exceeded 40. It is closely related to cell stress responses, cell statue, signal transduction, inflammasome activation, and other cellular processes [ 168 ]. Comprehensive molecular studies have shown that HUWE1 can target various substrates, including c-Myc [ 169 ].…”