| Property/Feature | Description | Evidence/Citations |
|---|---|---|
| Protein family | HERC3 is a member of the HERC subfamily of HECT-type E3 ubiquitin ligases. It belongs to the small HERC group together with HERC4, HERC5, and HERC6. HERC proteins are defined by a C-terminal HECT catalytic domain plus one or more RCC1-like domains (RLDs). | (pqac-00000005, pqac-00000006) |
| Molecular weight | Small HERC proteins, including HERC3, are reported to be ~100–120 kDa; HERC3 was described as encoding a protein of approximately 120 kDa. | (pqac-00000005, pqac-00000006) |
| Domain architecture | HERC3 contains an N-terminal RCC1-like domain (RLD) involved in substrate recognition/protein interactions and a C-terminal HECT domain containing the catalytic cysteine required for ubiquitin transfer. Deletion of either the HECT domain or the RLD impairs HERC3 function toward CFTR, and the RCC1 domain mediates interaction with EIF5A2. | (pqac-00000002, pqac-00000003, pqac-00000006) |
| Primary function | HERC3 functions as an E3 ubiquitin ligase that promotes ubiquitination and proteasome-dependent degradation of specific substrates. Recent work shows it defines an ER-associated degradation (ERAD) branch for select membrane proteins, while earlier studies showed roles in regulating MM1 stability and suppressing colorectal cancer metastasis via EIF5A2 degradation. | (pqac-00000001, pqac-00000002, pqac-00000004) |
| Enzymatic mechanism | As a HECT E3 ligase, HERC3 accepts ubiquitin from an E2 onto a catalytic cysteine intermediate and then transfers ubiquitin to substrate proteins. Catalytic dependence is demonstrated by loss of function of the C1018A mutant and by HECT-domain deletion. HERC3 was shown to promote K27- and K48-linked ubiquitination of EIF5A2, consistent with proteasomal targeting. | (pqac-00000000, pqac-00000002, pqac-00000003, pqac-00000006) |
| Known substrates | Experimentally supported substrates/clients include MM1, whose ubiquitination promotes degradation in the ΔNp63α/HERC3/MM1/c-Myc axis; EIF5A2, which is directly bound via the RCC1 domain and ubiquitinated for degradation; and misfolded membrane proteins such as ΔF508-CFTR, for which HERC3 promotes ubiquitination, retrotranslocation, and ERAD. | (pqac-00000001, pqac-00000002, pqac-00000003, pqac-00000004, pqac-00000013) |
| Subcellular localization | HERC3 shows a cytosolic distribution and, functionally, acts at the cytoplasmic face of the ER membrane during ERAD. It recognizes exposed membrane-spanning domains of misfolded CFTR and collaborates with ER quality-control components while remaining distinct from ER-embedded ligases RNF5/RNF185. | (pqac-00000005, pqac-00000004, pqac-00000012, pqac-00000013) |
| Key pathways | Key pathways/mechanistic contexts include: ER-associated degradation of select membrane proteins; regulation of cell senescence through the ΔNp63α/HERC3/MM1/c-Myc axis; and regulation of epithelial–mesenchymal transition and metastasis through EIF5A2/TGF-β/Smad2/3 signaling. In ERAD, HERC3 also facilitates recruitment of UBQLN factors downstream of substrate recognition. | (pqac-00000001, pqac-00000002, pqac-00000007, pqac-00000012) |


*Table: This table summarizes the core structural, enzymatic, cellular, and pathway-level properties of HERC3 E3 ubiquitin ligase from the literature used in this session. It is useful as a compact evidence-backed reference for functional annotation, especially when direct data for the target Drosophila ortholog are limited.*