Gene Ontology annotation through association of InterPro records with GO terms

Annotation inferences using phylogenetic trees

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

PMID:19805114

Suppression of retinal degeneration in Drosophila by stimulation of ER-associated degradation.

PMID:25716426

Role of Drosophila EDEMs in the degradation of the alpha-1-antitrypsin Z variant.

PMID:28633019

EDEM Function in ERAD Protects against Chronic ER Proteinopathy and Age-Related Physiological Decline in Drosophila.

Wild-type dEDEM2 overexpression reduces steady-state levels of the glycoprotein ERAD substrate NHK, whereas the catalytically inactive mutant E144Q (EF-hand motif mutation that abolishes alpha-1,2-mannosidase activity) instead increases NHK levels, indicating that mannosidase catalytic activity contributes to clearance of at least some glycoprotein ERAD substrates.

"dEDEM2 significantly reduced steady-state levels of NHK proteins, whereas the effect of dEDEM1 was modest (Figure 3D)."
EDEM mannosidase activity is dispensable for protection against chronic ER proteinopathy and age-related decline: catalytically inactive mutants E123Q and E144Q still reduced the non-glycoprotein substrate Abeta42 and suppressed neurodegenerative and locomotor phenotypes, supporting a mannosidase-independent (chaperone-like) substrate-engagement role in some contexts.

"E123Q and E144Q also significantly reduced Aβ42 levels, confirming that dEDEM mannosidase activity is not required for degradation of Aβ42, a non-glycoprotein substrate (Figure 3E)."

PMID:31553680

ER membrane protein complex is required for the insertions of late-synthesized transmembrane helices of Rh1 in Drosophila photoreceptors.

In Drosophila photoreceptors, loss of Edem1/Edem2 contributes to stabilization of some ERAD substrates (e.g. increased ER accumulation of TRP in a Syx5 background), but Edem-dependent ERAD is substrate-selective and does not account for degradation of all unstable photoreceptor proteins, with some client degradation in EMC-deficient cells being ERAD-independent.

"Rh1 was translated to its C terminus but degraded independently from"

file:DROME/Edem2/Edem2-deep-research-falcon.md

Falcon deep research report on Drosophila Edem2

Drosophila Edem2 (CG5682) is an ER-resident, GH47 / class I alpha-mannosidase-like ERAD factor (EDEM family) that promotes disposal of misfolded glycoprotein clients in the ER, improving proteostasis under proteotoxic burden.

"EDEM proteins (ER degradation-enhancing α-mannosidase-like proteins) are class I α-mannosidase-like factors (GH47-related) implicated in accelerating disposal of misfolded glycoproteins"
In Drosophila, overexpression of wild-type dEDEM2 reduces steady-state NHK protein levels whereas the catalytic mutant E144Q increases NHK, implying that mannosidase catalytic activity contributes to clearance of at least some glycoprotein ERAD substrates; some protective effects (e.g. against Abeta42) persist with catalytic mutants, implying additional non-enzymatic roles.

"overexpression of wild-type dEDEM2 reduced steady-state NHK protein levels, whereas a catalytically inactive mutant (E144Q) increased NHK levels, implying that **mannosidase-catalytic activity contributes to clearance of at least some glycoprotein ERAD substrates**"
Conserved mechanistic framing places EDEM2 at the first mannose-trimming step that initiates glycoprotein ERAD (gpERAD), acting on high-mannose N-glycans of misfolded glycoproteins (in mammals as an EDEM2-TXNDC11 complex), making this the most parsimonious model for Drosophila Edem2.

"EDEM2 is an **α1,2-mannose trimming enzyme** acting on **high-mannose N-glycans** of misfolded glycoproteins to promote gpERAD commitment"
Mammalian EDEM1/EDEM2 mannosidase activity is folding-state dependent, being much higher on unfolded/denatured glycoproteins (trimming toward smaller high-mannose species, M8 to M5), consistent with selective action on misfolded ER clients.

"EDEM2’s mannosidase activity is much higher on **unfolded/denatured glycoproteins**, trimming N-glycans to smaller high-mannose species (reported endpoints include M8→M5 species)"
In a Drosophila retinitis-pigmentosa model, Edem2 overexpression selectively reduced misfolded Rh-1G69D (not wild-type Rh-1), physically associated with Rh-1G69D, suppressed the xbp1-EGFP ER-stress reporter, and delayed retinal degeneration, indicating substrate-selective ER quality control upstream of UPR.

"Edem2 overexpression selectively reduced mutant Rh-1G69D levels (but not wild-type Rh-1), physically associated with Rh-1G69D, suppressed an ER-stress reporter (**xbp1-EGFP**), and delayed adult retinal degeneration"
Genetic analysis in photoreceptors shows Edem2-dependent ERAD is substrate-selective: loss of Edem1/Edem2 did not rescue EMC3-dependent loss of Rh1/TRP, indicating some client degradation is ERAD-independent while other substrates remain Edem-dependent.

"did not rescue EMC3-dependent losses of Rh1/TRP, supporting the conclusion that some client degradation is **ERAD-independent** while other substrates remain **Edem-dependent**"