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Review
. 2020 Apr 7;133(7):jcs228072.
doi: 10.1242/jcs.228072.

HECT E3 ubiquitin ligases - emerging insights into their biological roles and disease relevance

Yaya Wang  1   2 , Diana Argiles-Castillo  2 , Emma I Kane  2 , Anning Zhou  1 , Donald E Spratt  3
Affiliations
Review

HECT E3 ubiquitin ligases - emerging insights into their biological roles and disease relevance

Yaya Wang et al. J Cell Sci. .

Erratum in

Abstract

Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases play a critical role in various cellular pathways, including but not limited to protein trafficking, subcellular localization, innate immune response, viral infections, DNA damage responses and apoptosis. To date, 28 HECT E3 ubiquitin ligases have been identified in humans, and recent studies have begun to reveal how these enzymes control various cellular pathways by catalyzing the post-translational attachment of ubiquitin to their respective substrates. New studies have identified substrates and/or interactors with different members of the HECT E3 ubiquitin ligase family, particularly for E6AP and members of the neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4) family. However, there still remains many unanswered questions about the specific roles that each of the HECT E3 ubiquitin ligases have in maintaining cellular homeostasis. The present Review discusses our current understanding on the biological roles of the HECT E3 ubiquitin ligases in the cell and how they contribute to disease development. Expanded investigations on the molecular basis for how and why the HECT E3 ubiquitin ligases recognize and regulate their intracellular substrates will help to clarify the biochemical mechanisms employed by these important enzymes in ubiquitin biology.

Keywords: Cancer; Cell signaling; E3 ubiquitin ligase; HECT; Neurodegeneration; Neurodevelopmental disorders; Neurological disorders; Protein turnover; Protein-protein interactions; Ubiquitin; Ubiquitylation.

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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
HECT E3 ubiquitin ligases. (A) HECT E3 ligase-dependent ubiquitylation signaling pathway. Target proteins can be mono-, multi- or poly-ubiquitylated. (B) Crystal structure of the HECT domain of HUWE1 (PDB 3H1D; Pandya et al., 2010). The HECT domain, which is found all 28 members of the HECT E3 ubiquitin ligase family, consists of two lobes – the N-terminal lobe (green), which engages with a charged E2–ubiquitin, and the C-terminal lobe (blue), which contains the conserved catalytic cysteine residue (red) required for ubiquitylation activity. (C) HECT E3 ubiquitin ligase domain architecture. HECT E3 ligases can be categorized into three classes. The NEDD4 family members are characterized by their N-terminal Ca2+-binding C2 domain and WW domains that recognize PYXP sequences. Members of the HERC family contain one or two RCC1 domains. The ‘Other HECTs’ family members are more diverse and contain a variety of different protein–protein interaction domains, with some similarities and combinations of domains. HECT, homologous to E6AP C-terminus; C2, Ca2+ domain; WW, WW domain; HECWN, HECW1/2 N-terminal domain; H, helical bundle; SPRY, SPIA and ryanodine receptor domain; WD40, WD dipeptide domain; CYT-B5, cytochrome b5-like heme/steroid-binding domain; MIB, MIB/HERC2 domain; L2, ribosomal protein 2; ZNF, zinc finger; DOC, APC10/DOC domain; ARM, armadillo repeat-containing domain; UBA, ubiquitin-associated domain; WWE, WWE domain; BH2, Bcl-2 homology 3 domain; ANK, ankyrin-repeat domain; SUN, SAD1/UNC domain; MLLE, Mademoiselle/PABC domain; IGF, immunoglobulin-like fold; PHD, plant homeodomain-type zinc finger; AZUL, Zn-binding N-terminal domain; IQ, IQ motif/EF-hand binding site.
Fig. 2.
Fig. 2.
An overview of intracellular signaling pathway regulation by the HECT E3 ubiquitin ligases. Signaling pathways that are enhanced by a HECT E3 ubiquitin ligase are denoted with green arrows, while those that are downregulated are highlighted with a red cross. Details on the specific regulatory effect that some of the HECT E3 ubiquitin ligases have in the Wnt, TGF-β and Notch signaling pathways are shown in Fig. 3. There still remain many unanswered questions on the specific role(s) and/or function(s) that the HECT E3 ubiquitin ligases have in each of these pathways.
Fig. 3.
Fig. 3.
Molecular mechanisms used by members of the HECT E3 ubiquitin ligases to regulate Wnt, TGF-β and Notch signaling pathways. HUWE1, NEDD4L, ITCH, SMURF1, SMURF2 and HECTD1 downregulate Wnt signaling pathway either through mediating the ubiquitylation of Dvl or of Axin proteins. Conversely, UBR5 activates Wnt signaling by regulating the ubiquitylation of β-catenin, which results in enhanced β-catenin stability, as well as that of Groucho/TLE proteins, which inactivates this transcription repressor. SMURF1, SMURF2, WWP1 and NEDD4L E3 ubiquitin ligases suppress TGF-β signaling through promoting the ubiquitylation of Smad family members including Smad2, Smad3 and Smad7. In contrast, UBR5 upregulates TGF-β signaling by ubiquitylating Smad2 and Smad7. ITCH, NEDD4 and WWP2 inhibit Notch signaling by ubiquitylating Deltex (also known as DTX1), an E3 ubiquitin ligase that positively regulates Notch signaling, and targeting Deltex and Notch for proteosomal degradation. NEDD4, ITCH, WWP2 and UBR5 also inhibit the Notch signaling pathway by targeting Notch-like receptors GLP-1 and LIN-12 in C. elegans for degradation or inactivation.
Fig. 4.
Fig. 4.
Dysfunction of HECT E3 ligases is associated with various types of disease. Several HECT E3 ligases have been implicated in various types of cancers, neurodegenerative diseases and viral infections. Many of these diseases caused by HECT E3 ubiquitin ligase dysfunction have been genetically linked or caused by changes in protein expression, stability and/or ubiquitylation activity. Rare diseases have also been linked to HECT E3 ubiquitin ligase dysfunction including in autism, Wolfram syndrome, Kaufman oculocerebrofacial and X-linked intellectual disability, but the specific molecular basis for these phenotypes remain unclear and require further study.
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