| Topic | Claim | Evidence type | Key citation (year) | DOI / URL | Context ID(s) |
|---|---|---|---|---|---|
| Identity / target verification | Human **EDEM3** corresponds to UniProt **Q9BZQ6**; aliases include **C1orf22** and the protein is **ER degradation-enhancing alpha-mannosidase-like protein 3**, a GH47-family EDEM protein involved in ERAD. | Primary, review, database | Olivari et al. 2005; Manica et al. 2021; Open Targets | https://doi.org/10.1074/jbc.c400534200 ; https://doi.org/10.3390/ijms22042172 ; https://platform.opentargets.org/target/ENSG00000116406 | (pqac-00000020, pqac-00000000) |
| Domains and motifs | EDEM3 is a **931 aa** soluble ER protein with four modules: **GH47** mannosidase-like domain, **IMD** (intermediate) domain, **PA** (protease-associated) domain, **IDD** (intrinsically disordered domain), plus a C-terminal **KDEL** ER-retention motif. Figure-based domain schematic explicitly shows these modules and KDEL. | Primary, figure evidence | Manica et al. 2021 | https://doi.org/10.3390/ijms22042172 | (pqac-00000020, pqac-00000022) |
| Localization / topology | EDEM3 is described as a **soluble ER luminal / ER-localized** protein retained by **KDEL**, rather than a membrane-anchored ERAD factor. | Primary, review | Hirao et al. 2006; Manica et al. 2021 | https://doi.org/10.1074/jbc.m512191200 ; https://doi.org/10.3390/ijms22042172 | (pqac-00000017, pqac-00000020) |
| Enzyme class / catalytic function | EDEM3 is a **GH47 class I α1,2-mannosidase-like** enzyme; overexpression stimulates mannose trimming, and catalytic-site mutation **E147Q** abolishes trimming and markedly reduces ERAD enhancement, supporting bona fide α1,2-mannosidase activity in vivo. UniProt annotates **EC 3.2.1.113**. | Primary, review, database | Hirao et al. 2006; Słomińska-Wojewódzka & Sandvig 2015; UniProt-derived target description | https://doi.org/10.1074/jbc.m512191200 ; https://doi.org/10.3390/molecules20069816 ; https://www.uniprot.org/uniprotkb/Q9BZQ6 | (pqac-00000015, pqac-00000018) |
| Glycan substrates / processing step | EDEM3 acts on **N-linked high-mannose glycans** on misfolded glycoproteins in ER quality control. It participates after EDEM2 in sequential mannose trimming and contributes to formation of ERAD-targeting glycans; reviews place EDEM-mediated trimming in generation of signals recognized by downstream lectins. | Primary, review | Manica et al. 2021; Christianson et al. 2023 | https://doi.org/10.3390/ijms22042172 ; https://doi.org/10.1038/s41580-023-00633-8 | (pqac-00000020, pqac-00000012) |
| Branch specificity / reaction detail | Primary biochemical work indicates EDEM3-mediated trimming can convert **M8B to M7A** by removing a terminal mannose from branch C, but activity is weak on purified free glycans and much more effective on misfolded glycoprotein substrates in cells or reconstituted systems. | Primary | Yu et al. 2018 | https://doi.org/10.1074/jbc.ra118.003129 | (pqac-00000005) |
| Model substrates | Experimentally supported glycoprotein substrates/clients used to study EDEM3 include **TCRα**, **α1-antitrypsin NHK**, **ATZ**, soluble tyrosinase mutant, and other misfolded N-glycoproteins. | Primary | Hirao et al. 2006; Yu et al. 2018; Manica et al. 2021 | https://doi.org/10.1074/jbc.m512191200 ; https://doi.org/10.1074/jbc.ra118.003129 ; https://doi.org/10.3390/ijms22042172 | (pqac-00000015, pqac-00000002, pqac-00000004) |
| Interaction partners | **ERp46/TXNDC5** is the best-supported functional partner: it stably associates with EDEM3 and **triggers** EDEM3 mannose-trimming activity through a redox-dependent covalent interaction. Proteomics also identified few stable partners, including **SEL1L, BiP/HSPA5, DNAJB9, UFD1**, consistent with mainly transient substrate interactions. | Primary | Yu et al. 2018; Manica et al. 2021 | https://doi.org/10.1074/jbc.ra118.003129 ; https://doi.org/10.3390/ijms22042172 | (pqac-00000002, pqac-00000001, pqac-00000006) |
| Redox regulation | EDEM3 enzymatic function is linked to **ER redox chemistry**: ERp46 redox-active cysteines form a disulfide-linked complex with the EDEM3 mannosidase domain, enabling reconstitution of trimming activity toward misfolded TCRα in vitro. | Primary | Yu et al. 2018 | https://doi.org/10.1074/jbc.ra118.003129 | (pqac-00000005) |
| Pathway role in gpERAD | EDEM3 functions in **glycoprotein ER-associated degradation (gpERAD)** by recognizing misfolded glycoproteins, trimming their mannose residues, helping terminate futile calnexin/calreticulin folding cycles, and promoting commitment to degradation. | Primary, review | Hirao et al. 2006; Słomińska-Wojewódzka & Sandvig 2015; Christianson et al. 2023 | https://doi.org/10.1074/jbc.m512191200 ; https://doi.org/10.3390/molecules20069816 ; https://doi.org/10.1038/s41580-023-00633-8 | (pqac-00000015, pqac-00000018, pqac-00000012) |
| Domain-specific functional interpretation | The **GH47** domain is sufficient for substrate binding but requires **IMD** for proper folding; **PA** and **IDD** are not essential for trimming per se but modulate turnover kinetics of specific substrates, implying EDEM3 influences ERAD timing and client selectivity. | Primary | Manica et al. 2021 | https://doi.org/10.3390/ijms22042172 | (pqac-00000006, pqac-00000004) |
| Structural/biophysical behavior | EDEM3 sediments in fractions consistent with roughly **120–250 kDa** species, compatible with homo-/hetero-dimeric assemblies; its interactome is relatively sparse compared with EDEM1, supporting a model of transient client engagement. | Primary | Manica et al. 2021 | https://doi.org/10.3390/ijms22042172 | (pqac-00000001, pqac-00000004) |
| Recent mechanistic context (2023–2024) | Recent ERAD literature emphasizes that glycoprotein fate reflects a **tug-of-war between folding (UGGT/CNX-CRT cycle) and degradation (EDEM-mediated demannosylation)**; EDEM3 is part of this decision module in current models of mammalian ER quality control. | Review / primary preprint | Christianson et al. 2023; Ninagawa et al. 2024 | https://doi.org/10.1038/s41580-023-00633-8 ; https://doi.org/10.1101/2023.10.18.562958 | (pqac-00000012, pqac-00000014) |
| Disease association: congenital disorder of glycosylation | Open Targets links EDEM3 to **congenital disorder of glycosylation** and specifically **CDG type 2V**, with a relatively high association score (~**0.774** for CDG and ~**0.767** for CDG type 2V) based on curated evidence. | Database / genetics curation | Open Targets | https://platform.opentargets.org/target/ENSG00000116406 | (pqac-00000000) |
| Disease association: other phenotype terms | Open Targets also lists evidence linking EDEM3 to **short stature**, **bronchiectasis**, and **systemic lupus erythematosus**, though these associations are weaker (scores ~**0.31–0.32**) and should be interpreted more cautiously than the CDG association. | Database | Open Targets | https://platform.opentargets.org/target/ENSG00000116406 | (pqac-00000000) |
| Disease association: HBV/HCC | In hepatocellular carcinoma studies, EDEM3 is reported as **upregulated in HCC tissues**, highest in **HBV-infected** tumors; mechanistically, EDEM3 overexpression attenuated UPR and promoted secretory autophagy/HBV production, whereas depletion increased ER stress and apoptosis. | Primary | Ghionescu et al. 2025 | https://doi.org/10.1186/s12929-024-01103-9 | (pqac-00000009) |
| Disease association: cancer prognosis | Review literature cites Human Protein Atlas-based observations that **high EDEM3 expression** is associated with **unfavorable prognosis in renal cancers**, supporting broader relevance of ERQC/ERAD adaptation in malignancy. | Review | Tax et al. 2019 | https://doi.org/10.1155/2019/8384913 | (pqac-00000000) |
| Human genetics / metabolic trait association | A large multi-ancestry **random glucose GWAS** in **476,326** individuals identified **EDEM3** as a locus with a **low-frequency coding variant** associated with glucose regulation, nominating EDEM3 as a plausible glucose-homeostasis gene. | Primary genetics | Lagou et al. 2023 | https://doi.org/10.1038/s41588-023-01462-3 | (pqac-00000011) |


*Table: This table summarizes the main experimentally supported and clinically relevant features of human EDEM3/Q9BZQ6, including identity, domain organization, ER localization, catalytic role in gpERAD, interaction partners, and disease or genetics associations. It is designed as a compact citation map for use in a full research report.*