| 2007 |
HERC4 E3 ubiquitin ligase is required for proper maturation of spermatozoa and removal of the cytoplasmic droplet; male mice homozygous for a Herc4 mutation show ~50% reduced fertility with abnormal spermatozoa retaining cytoplasmic droplets at tail angulations, establishing a role for HERC4 in the ubiquitin-proteasome-dependent remodeling during spermiogenesis. |
Knockout mouse model (homozygous Herc4 mutation), histological analysis of testis and sperm morphology, fertility assays |
Developmental Biology |
High |
17967448
|
| 2016 |
HERC4 interacts with the transcription factor c-Maf and catalyzes its K48-linked polyubiquitination at residues K85 and K297, leading to proteasome-mediated degradation of c-Maf; this ubiquitination is counteracted by the deubiquitinase USP5. |
Affinity chromatography, mass spectrometry, co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K85R, K297R), in vitro and in vivo xenograft models |
Blood |
High |
26825710
|
| 2015 |
Drosophila Herc4 (HECT domain E3 ligase) directly ubiquitylates and destabilizes the Hippo pathway scaffold protein Salvador (Sav); Hippo kinase activity antagonizes Herc4-mediated Sav degradation by reducing the Sav/Herc4 interaction in a kinase-dependent manner, creating a positive feedback loop. |
Cell-based RNAi screen, ubiquitylation assay, co-immunoprecipitation, genetic epistasis in Drosophila, kinase-dead Hippo mutants |
PLoS ONE |
High |
26125558
|
| 2019 |
HERC4 acts as an E3 ligase for the tumor suppressor LATS1, promoting its ubiquitination and proteasomal degradation, thereby inactivating the Hippo pathway and promoting breast tumorigenesis; miR-136-5p and miR-1285-5p suppress HERC4 expression. |
Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression in breast cancer cell lines, in vivo xenograft tumor growth assay |
Protein & Cell |
Medium |
30710319
|
| 2019 |
HERC4 binds to Smoothened (Smo) and promotes its ubiquitination and proteasomal degradation, thereby negatively regulating Hedgehog signaling; this degradation is modulated by Hh signaling through PKA-primed phosphorylation-dependent and -independent mechanisms. |
Co-immunoprecipitation, ubiquitination assay, Drosophila modifier screen, Hh pathway reporter assays, knockdown/overexpression in mammalian cells |
Journal of Molecular Cell Biology |
High |
30925584 31010679
|
| 2019 |
Drosophila dHerc4 degrades dSmo (Smoothened) and depletion of dherc4 increases dSmo protein levels and activates the Hedgehog pathway; human HERC4 reciprocally interacts with Smo in NSCLC cells and knockdown of HERC4 activates Hh pathway and promotes NSCLC cell proliferation. |
Drosophila genetic modifier screen, co-immunoprecipitation (reciprocal), knockdown in NSCLC cell lines, Hh pathway reporter assay |
Biochemical and Biophysical Research Communications |
Medium |
31010679
|
| 2021 |
HERC4 directly downregulates SAV1 (Salvador 1) protein levels in hepatocellular carcinoma cells, as demonstrated by co-immunoprecipitation and the ability of HERC4 overexpression to reverse the tumor-suppressive effects of SAV1. |
Co-immunoprecipitation, RT-qPCR, Western blot, immunofluorescence, functional assays (EdU, colony formation, Transwell), xenograft model |
Translational Cancer Research |
Medium |
35116265
|
| 2023 |
HERC4 interacts with MafA and mediates atypical K63-linked polyubiquitination at K33, which inhibits GSK3β-triggered MafA phosphorylation and transcriptional activity (instead of promoting degradation); a K33R MafA variant prevents HERC4 from inhibiting MafA phosphorylation. HERC4 also suppresses MafA-activated STAT3 signaling. |
Co-immunoprecipitation, ubiquitination assay with linkage-specific analysis, site-directed mutagenesis (K33R), phosphorylation assay, STAT3 reporter assay, xenograft model |
Journal of Biological Chemistry |
High |
37028761
|
| 2024 |
The small molecule AK59 induces STING degradation by recruiting the E3 ligase HERC4 (a HECT-domain protein) to ubiquitinate and degrade STING via the ubiquitin-proteasome system; AK59 is effective on common pathological STING mutations. |
Targeted protein degradation (TPD) assay, compound-induced ubiquitination, proteasome inhibitor rescue, mechanistic characterization with HERC4 knockdown/knockout |
Nature Communications |
High |
38811577
|
| 2025 |
HERC4 interacts with KRT19 (cytokeratin 19) and promotes its ubiquitination, leading to KRT19 downregulation in lung adenocarcinoma; KRT19 loss drives EMT and increases metastatic potential. |
Co-immunoprecipitation, GST pull-down assay, ubiquitination assay, CCK-8, wound healing, Transwell assay, mouse model |
Translational Oncology |
Medium |
41192149
|
| 2024 |
HERC4 overexpression in ovarian cancer cells reduces SMO protein levels and inhibits downstream Hedgehog signaling pathway components, suppressing cell proliferation in vitro and tumor growth in vivo. |
Lentiviral overexpression, CCK-8 cell viability assay, Western blot, RT-PCR, xenograft tumor model |
Biochimica et Biophysica Acta - General Subjects |
Low |
38181892
|
| 2024 |
METTL3 interacts with HERC4 (demonstrated by co-immunoprecipitation) in hepatocellular carcinoma cells; METTL3 overexpression upregulates HERC4 expression, and HERC4 overexpression can reverse the effects of METTL3 silencing on HCC cell proliferation and migration. |
Co-immunoprecipitation, m6A quantification, immunofluorescence, proliferation/migration assays, immunoblotting |
Cancer Biotherapy & Radiopharmaceuticals |
Low |
39611657
|