EDEM3 (Q9BZQ6) review notes

Identity

• ER degradation-enhancing alpha-mannosidase-like protein 3. ER lumenal protein (signal peptide; PROSITE PRU10138 ER retention). GH47 family (EDEM1/2/3). Contains a protease-associated (PA) domain of unknown function (distinguishes EDEM3 from EDEM1/2). EC 3.2.1.113.

Function (synthesis)

• EDEM3 is an active alpha-1,2-mannosidase that accelerates glycoprotein ERAD by catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 (the second/downstream trimming step), and further to Man5 isomers [UniProt FUNCTION "Accelerates the glycoprotein ERAD by proteasomes, by catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans (PubMed:25092655)"; CATALYTIC ACTIVITY RHEA:56008 (M9 isomer 9A1,2,3B1,2,3 -> M5A1,2 + 4 mannose) and RHEA:56028 (M8 -> M5 + 3 mannose), EC=3.2.1.113].
• Endogenous KO analysis: EDEM3 (mainly) and EDEM1 (to a lesser extent) perform the second trimming step Man8B->Man7 [PMID:25092655 "Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1"; "M8B is trimmed by EDEM1 and EDEM3 to Man7-5GlcNAc2, which are recognized by lectin OS-9"]. EDEM3 acts downstream of EDEM2.
• Unlike EDEM2, EDEM3 (with EDEM1) binds SEL1L PMID:25092655.
• May also trim N-glycans on all glycoproteins, not just misfolded ERAD substrates [UniProt FUNCTION "May also participate in mannose trimming from all glycoproteins and not just misfolded ones targeted to ERAD (PubMed:34143952)"].
• Disease: biallelic variants cause Congenital disorder of glycosylation 2V (CDG2V/EDEM3-CDG), autosomal recessive neurodevelopmental delay [UniProt DISEASE; PMID:34143952, not cached but recorded in UniProt].
• Calcium cofactor (Ca2+) required (GH47 fold) [UniProt COFACTOR].

Localization

• ER lumen [UniProt SUBCELLULAR LOCATION; IEA]. ER [IEA].

Annotation review decisions

• GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity: CORE. IBA, IEA (with EC 3.2.1.113/RHEA), TAS Reactome, ISS, IMP (PMID:25092655) — all ACCEPT. EDEM3 has the strongest/clearest catalytic activity of the three EDEMs (no NOT annotation). Core MF.
• GO:1904380 ER mannose trimming: IMP (PMID:25092655) ACCEPT core; IEA ACCEPT.
• GO:0036503 ERAD pathway: IMP (PMID:25092655) ACCEPT core; IEA ACCEPT.
• GO:1904382 mannose trimming involved in glycoprotein ERAD pathway (TAS Reactome): ACCEPT core.
• GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway (IBA): ACCEPT, specific/correct.
• GO:0006516 glycoprotein catabolic process (IEA ARBA): correct but generic parent of gpERAD; KEEP_AS_NON_CORE / could MARK_AS_OVER_ANNOTATED. Use ACCEPT-adjacent: it is reasonably specific (glycoprotein catabolism) -> KEEP_AS_NON_CORE.
• GO:0030968 ER unfolded protein response (IBA): UPR-induced effector acting in ERAD; KEEP_AS_NON_CORE.
• GO:0005509 calcium ion binding (IEA): GH47 cofactor; KEEP_AS_NON_CORE.
• GO:0005788 ER lumen (IEA), GO:0005783 ER (IEA): ACCEPT.
• GO:0044322 ERQC (TAS Reactome): ACCEPT.
• GO:0005975 carbohydrate metabolic process (IEA), GO:0016020 membrane (IEA): over-general/inaccurate (EDEM3 is luminal, not membrane) -> MARK_AS_OVER_ANNOTATED.
  

Falcon deep-research findings (incorporated 2026-06)

• Hirao et al. 2006 (JBC) is the original EDEM3 characterization (was previously only referenced via UniProt): EDEM3 is a 931-aa soluble Class I GH47 alpha-mannosidase homolog with a C-terminal protease-associated (PA) motif; overexpression accelerates gpERAD of misfolded A1AT-NHK and TCRalpha and stimulates mannose trimming from misfolded AND total glycoproteins; the catalytic E147Q mutant abolishes trimming and decreases ERAD enhancement, proving in vivo alpha-1,2-mannosidase activity PMID:16431915. Notably distinguishes EDEM3 from EDEM (EDEM1) "which has no apparent alpha1,2-mannosidase activity."
• Yu et al. 2018 (JBC): the ER oxidoreductase ERp46 (TXNDC5) triggers EDEM3 mannose-trimming activity. ERp46 stably associates with EDEM3 via a disulfide bond between ERp46 redox-active cysteines and the EDEM3 alpha-mannosidase domain; this redox-dependent covalent interaction is REQUIRED to reconstitute EDEM3 trimming of misfolded TCRalpha in vitro PMID:29784879. This is the EDEM3 analog of the EDEM2-TXNDC11 redox pair (George 2020) - both EDEMs are gated by a disulfide-linked ER oxidoreductase.
• Manica et al. 2021 (IJMS): EDEM3 has four cooperating modules - GH47 (mannosidase, substrate binding), IMD (intermediate, needed for GH47 folding), PA (protease-associated), and IDD (intrinsically disordered). GH47 binds substrate even without trimming; PA and IDD do not affect trimming per se but modulate ERAD turnover timing of specific clients (NHK, soluble tyrosinase mutant). Few stable ER interactors -> transient substrate engagement PMID:33671632. Defines EDEM3's role in setting ERAD timing/client selectivity.
• Ghionescu et al. 2025 (J Biomed Sci): EDEM3 is upregulated in HCC, highest in HBV-infected tumors, associated with progression/poor prognosis; EDEM3 overexpression attenuates UPR and activates secretory autophagy promoting HBV production, while depletion induces ER stress and apoptosis PMID:39838427. Pro-survival/pro-viral disease role.
• Lagou et al. 2023 (Nat Genet, PMID resolvable but NOT added): cross-ancestry random-glucose GWAS in 476,326 individuals nominated the EDEM3 locus (low-frequency coding variant) for glucose homeostasis - a genetic association, not a molecular-function finding, so notes-only.
• References ADDED to review: PMID:16431915 (Hirao 2006, HIGH), PMID:29784879 (Yu 2018, HIGH), PMID:33671632 (Manica 2021, HIGH), PMID:39838427 (Ghionescu 2025, MEDIUM). PMID:16431915 and PMID:29784879 added (id only, uncached) to core_function supported_by.