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

Wang, Yaya; Argiles-Castillo, Diana; Kane, Emma I.; Zhou, Anning; Spratt, Donald E.

doi:10.1242/jcs.228072

Cited by 98 publications

(102 citation statements)

References 170 publications

(186 reference statements)

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“…With new research and discoveries becoming available, there is mounting evidence that the lesser known HECT E3 ubiquitin ligases play critical roles in regulating intracellular processes and their dysfunction have been suggested to contribute to the onset of many diseases and disorders [4,[29][30][31][32]. Here we discuss the latest discoveries on these lesser known members of the HECT E3 ubiquitin ligases and on their emerging roles in developmental and neurological abnormalities, cancers, and embryogenesis.…”

Section: The "Other" Hect E3 Ubiquitin Ligases: Important Players Inmentioning

confidence: 98%

“…E3 ubiquitin ligases play an important role in recognizing, binding, and covalently attaching ubiquitin to their various substrates to elicit a specific cellular response [3]. The homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases are a unique subfamily that use a multistep pathway to selectively target substrate proteins for ubiquitylation [4]. HECT-dependent ubiquitylation requires the recruitment of an E2 ubiquitin conjugating enzyme charged with ubiquitin to the N-terminal lobe of the HECT domain on the E3 ligase [5,6].…”

Section: Hect E3 Ubiquitin Ligase-dependent Ubiquitylationmentioning

confidence: 99%

“…The HECT E3 ubiquitin ligases can be categorized into three subfamilies -NEDD4, HERC, and "other" -based on their sequence/structure similarity and domain architecture [4,5]. Of the 28 HECT E3 ubiquitin ligases identified in humans, there are 12 "other" HECT E3 ubiquitin ligases that do not fall under the well-studied NEDD4 or HERC subfamilies.…”

Section: The "Other" Hect E3 Ubiquitin Ligases: Important Players Inmentioning

confidence: 99%

“…Of the 28 HECT E3 ubiquitin ligases identified in humans, there are 12 "other" HECT E3 ubiquitin ligases that do not fall under the well-studied NEDD4 or HERC subfamilies. Each member of the "other" HECTs have variable N-terminal domains that are thought to be involved in protein-protein interactions and/or intracellular localization [4,5]. Having prominent responsibilities in cellular homeostasis would leave the impression there is ample research on the HECT E3 ubiquitin ligase family as a whole, however, there remain many unanswered questions about the biological functions and mechanisms of this important E3 ligase family, particularly for members of the more mysterious "other" subfamily.…”

Section: The "Other" Hect E3 Ubiquitin Ligases: Important Players Inmentioning

confidence: 99%

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New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

Kane¹,

Spratt²

2020

Ubiquitin - Proteasome Pathway

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HECT E3 ubiquitin ligases selectively recognize, bind, and ubiquitylate their substrate proteins to target them for 26S proteasomal degradation. There is increasing evidence that HECT E3 ubiquitin ligase dysfunction due to misfolding and/or the gene encoding the protein being mutated is responsible for the development of different diseases. Apart from the more prominent and well-characterized E6AP and members of the NEDD4 family, new studies have begun to reveal how other members of the HECT E3 ubiquitin ligase family function as well as their links to disease and developmental disorders. This chapter provides a comprehensive discussion on the more mysterious members of the HECT E3 ubiquitin ligase family and how they control intracellular processes. Specifically, AREL1, HACE1, HECTD1, HECTD4, G2E3, and TRIP12 will be examined as these enzymes have recently been identified as contributors to disease development.2 covalently attach ubiquitin on to a lysine residue of the substrate protein forming a stable isopeptide bond between the C-terminus of ubiquitin and the ε-amine of the substrate lysine [3,5,6]. This process can be repeated numerous times to form different polyubiquitin chain linkages with the specific HECT E3 ubiquitin ligase dictating the type(s) of ubiquitin linkages that are built [2,7]. Chain typesLinker Proposed function Monoubiquitylation Monoubiquitylation/ multi-monoubiquitylation Endocytosis [9] DNA damage repair [10-15] Histone regulation [10-15] Mitophagy [10-15] Protein localization [10-15] Protein interactions [10-15] Protein transportation [10-15] Transcription activation [10-15] Polyubiquitylation Chain (homotypic) M1 Innate immunity [2, 9, 16] Linear chain formation [9] NF-κB activation [9, 16] Signaling cascades [9, 16] K6 DNA damage response [14] NF-κB regulation [14] Mitophagy [14] K11 Cell cycle regulation [17] DNA damage response [18] Mitophagy [17] NF-κB activation [16] Protein degradation [17] K27 DNA damage response [18] Kinase activation [19] Protein degradation [20] Protein scaffolding [21] Protein trafficking [22] K29 DNA damage response [18] Kinase activation [19] Protein degradation [9] K33 DNA damage response [10-15, 18] Kinase activation [23] Post-golgi trafficking [24] T-cell signaling [23] K4 8 Protein degradation [1, 2, 25] K63 DNA damage response [9, 18] NF-κB activation [9, 16] Protein trafficking [9] Chain (heterotypic; branched) M1 /K63 NF-κB activation [16] K11 /K4 8 Protein degradation [26, 27] K29/K48 Protein degradation [26] K48/K63 Protein degradation [26] K11 /K63 Endocytosis [28]

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Section: The "Other" Hect E3 Ubiquitin Ligases: Important Players Inmentioning

confidence: 98%

Section: Hect E3 Ubiquitin Ligase-dependent Ubiquitylationmentioning

confidence: 99%

Section: The "Other" Hect E3 Ubiquitin Ligases: Important Players Inmentioning

confidence: 99%

Section: The "Other" Hect E3 Ubiquitin Ligases: Important Players Inmentioning

confidence: 99%

See 2 more Smart Citations

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

Kane¹,

Spratt²

2020

Ubiquitin - Proteasome Pathway

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“…Mutations in HUWE1 cause heterogenous neurodevelopmental XLID syndromes. To determine the common process that underlies HUWE1-promoted XLID, and since HUWE1 regulates multiple transcription factors important for neurodevelopment (19), we performed the RNA sequencing analysis. The transcriptomes from five XLID patient-derived LCLs, harboring different HUWE1 mutations were compared with the transcriptomes from four healthy age-and sex-matched LCLs.…”

Section: Huwe1mentioning

confidence: 99%

Increased p53 signaling impairs neural differentiation causing HUWE1-promoted intellectual disabilities

Aprigliano

Bradamante

Mihaljevic

et al. 2020

Preprint

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Essential E3 ubiquitin ligase HUWE1 (HECT, UBA and WWE domain containing 1) regulates key factors, as p53. Mutations in HUWE1 have been associated with neurodevelopmental Xlinked intellectual disabilities (XLIDs), however the pathomechanism at the onset of heterogenous XLIDs remains unknown. In this work, we identify p53 signaling as the process hyperactivated in lymphoblastoid cells from patients with HUWE1-promoted XLIDs. The hiPSCs-based modeling of the severe HUWE1-promoted XLID, the Juberg Marsidi syndrome (JMS), reviled majorly impaired neural differentiation, accompanied by increased p53 signaling. The impaired differentiation results in loss of cortical patterning and overall undergrowth of XLID JMS patient-specific cerebral organoids, thus closely recapitulating key symptoms, as microcephaly. Importantly, the neurodevelopmental potential of JMS hiPSCs is successfully rescued by restoring p53 signaling, upon reduction of p53 levels. In summary, our findings indicate that increased p53 signaling leads to impaired neural differentiation and is the common cause of neurodevelopmental HUWE1-promoted XLIDs.

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A Pro‐Fluorescent Ubiquitin‐Based Probe to Monitor Cysteine‐Based E3 Ligase Activity

Pérez Berrocal,

Vishwanatha,

Horn‐Ghetko

et al. 2023

Angewandte Chemie

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Protein post-translational modification with ubiquitin (Ub) is a versatile signal regulating almost all aspects of cell biology, and an increasing range of diseases is associated with impaired Ub modification. In this light, the Ub system offers an attractive, yet underexplored route to the development of novel targeted treatments. A promising strategy for small molecule intervention is posed by the final components of the enzymatic ubiquitination cascade, E3 ligases, as they determine the specificity of the protein ubiquitination pathway. Here, we present UbSRhodol, an autoimmolative Ub-based probe, which upon E3 processing liberates the pro-fluorescent dye, amenable to profile the E3 transthiolation activity for recombinant and in cellextract E3 ligases. UbSRhodol enabled detection of changes in transthiolation efficacy evoked by enzyme key point mutations or conformational changes, and offers an excellent assay reagent amenable to a highthroughput screening setup allowing the identification of small molecules modulating E3 activity.

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

Cited by 98 publications

References 170 publications

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

Increased p53 signaling impairs neural differentiation causing HUWE1-promoted intellectual disabilities

A Pro‐Fluorescent Ubiquitin‐Based Probe to Monitor Cysteine‐Based E3 Ligase Activity

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