| Evidence type | Key finding | Experimental system | Quantitative/statistical details | Interpretation for Edem2 function | Source (short citation) | URL |
|---|---|---|---|---|---|---|
| Genetic/biochemical/phenotype | **Identity verified:** Drosophila **Edem2 = CG5682**; homologous to mammalian EDEM2/EDEM3 and yeast Htm1p; belongs to GH47/class I α-mannosidase-like ERAD factors | Drosophila sequence comparison and ERAD functional assays in eye disc/S2 cell models | Homology-based assignment; no direct kinetic value reported in this excerpt (pqac-00000019, pqac-00000023) | Supports that Q9VK27 is the correct **D. melanogaster Edem2** and that its expected core role is glycoprotein quality control in ERAD | Kang 2009 PNAS | https://doi.org/10.1073/pnas.0905566106 |
| Biochemical | Edem2 overexpression selectively reduces **misfolded Rh-1G69D**, but not wild-type Rh-1; also downregulates luminal ERAD substrate **α1-antitrypsin NHK** | Drosophila larval eye imaginal discs; S2 cells; transgenic overexpression | Rh-1G69D reduction quantified with **n=6**; NHK reduction qualitative in excerpt (pqac-00000018, pqac-00000019) | Edem2 acts on **misfolded ER clients**, including both membrane and luminal substrates, consistent with a substrate-selective ERAD factor | Kang 2009 PNAS | https://doi.org/10.1073/pnas.0905566106 |
| Biochemical | Edem2 physically **co-immunoprecipitates with Rh-1G69D but not Rh-1WT** | Drosophila S2 cell co-IP | Interaction is substrate-selective; quantitative binding constants not reported (pqac-00000018, pqac-00000019) | Strong evidence that Edem2 preferentially recognizes aberrant conformers rather than normal Rh1 | Kang 2009 PNAS | https://doi.org/10.1073/pnas.0905566106 |
| Phenotype/UPR readout | Edem2 suppresses **ER stress** caused by Rh-1G69D, measured by **xbp1-EGFP** splicing reporter | Drosophila eye imaginal discs | **xbp1-EGFP suppression n=3, P=0.0052**; no suppression reported for Rh-1WT-driven signal (pqac-00000018) | Edem2 lowers burden of misfolded ER proteins, likely by promoting their disposal before they trigger strong UPR signaling | Kang 2009 PNAS | https://doi.org/10.1073/pnas.0905566106 |
| Phenotype | Edem2 delays **retinal degeneration** in the ADRP model **ninaE^G69D/+** | Adult Drosophila retina/pseudopupil and rhabdomere analyses | At 28 d, **64.43 ± 11.11%** retained intact pseudopupils with Edem2 vs ~**10.47 ± 8.46%** lacZ control; **n=4, P=0.0002**. Ommatidia retaining all 7 rhabdomeres: **68.9 ± 16.1%**, **n=3** (pqac-00000018) | In vivo evidence that increasing Edem2-mediated ER quality control is protective against chronic rhodopsin proteotoxicity | Kang 2009 PNAS | https://doi.org/10.1073/pnas.0905566106 |
| Genetic/biochemical | Wild-type dEDEM2 reduces steady-state **NHK** levels, whereas catalytic mutant **E144Q** increases NHK levels | Drosophila neuronal overexpression assays with ERAD substrate NHK | Significant effects reported; exact fold-change not included in excerpt (pqac-00000002, pqac-00000016) | Indicates **mannosidase activity contributes to glycoprotein ERAD substrate clearance** by dEDEM2 | Sekiya 2017 Dev Cell | https://doi.org/10.1016/j.devcel.2017.05.019 |
| Biochemical/phenotype | dEDEM2 lowers **Aβ42** levels and suppresses Aβ42-induced locomotor and neurodegenerative phenotypes; catalytically inactive mutants retain protection | Drosophila neuronal Aβ42 ER proteinopathy model; co-IP with Aβ42 | Protective effects significant; exact behavioral values not in excerpt. Catalytic mutants **E123Q/E144Q** still reduced Aβ42 and protected (pqac-00000002, pqac-00000016) | Suggests dEDEM2 has both **mannosidase-dependent ERAD activity** (for glycoproteins like NHK) and **mannosidase-independent/chaperone-like activity** for some nonglycosylated toxic ER proteins | Sekiya 2017 Dev Cell | https://doi.org/10.1016/j.devcel.2017.05.019 |
| Phenotype/aging | dEDEM2 overexpression improves age-associated physiology; neuronal overexpression modestly extends lifespan, gut overexpression extends lifespan more strongly | Adult Drosophila overexpression in neurons, muscle, and midgut | Neuronal median lifespan **47 → 50 d**; muscle **67 → 64 d**; midgut **67 → 76 d**. Locomotor benefits significant; lifespan by log-rank, sample sizes ~**n=190–306** depending on assay (pqac-00000015, pqac-00000017) | Boosting Edem2-linked ERAD capacity can improve organismal proteostasis during aging, with tissue-specific benefit | Sekiya 2017 Dev Cell | https://doi.org/10.1016/j.devcel.2017.05.019 |
| Mechanistic/UPR | Chronic dEDEM overexpression protects without broad canonical UPR activation; aging is associated with slower ERAD substrate turnover | Adult Drosophila brains | Aging slows NHK degradation and causes CD3d-YFP accumulation; overexpression had minimal PERK/Xbp1-RB induction in excerpt (pqac-00000001, pqac-00000014, pqac-00000015) | Supports Edem2 as an **ERAD enhancer**, not simply a general UPR activator | Sekiya 2017 Dev Cell | https://doi.org/10.1016/j.devcel.2017.05.019 |
| Genetic | Loss of Edem1/Edem2 contributes to stabilization of some ERAD substrates in photoreceptors, but does **not** rescue EMC-dependent Rh1/TRP loss | Drosophila photoreceptors; Edem1/Edem2 alleles combined with Syx5 or EMC3 mutants | TRP accumulation ratio: **Syx5 single 0.95 ± 0.25** vs **Syx5, Edem1, Edem2 triple 1.64 ± 0.30**. EMC3Δ6 TRP ratio: **0.42 ± 0.05** vs **0.46 ± 0.08** in triple mutant (pqac-00000021) | Edem2 participates in photoreceptor **ERAD**, but some client degradation in EMC-deficient cells is **ERAD-independent**, refining substrate scope | Hiramatsu 2019 Mol Biol Cell | https://doi.org/10.1091/mbc.e19-08-0434 |
| Genetic/substrate specificity | In EMC3-deficient photoreceptors, Edem1/Edem2 loss allows **NaKβ** accumulation but not rescue of Rh1, NaKα, or TRP | Drosophila photoreceptor genetics | Qualitative substrate selectivity; ratio values above for TRP (pqac-00000021) | Implies Edem2-dependent ERAD is **substrate-selective**, not universally responsible for degradation of all unstable photoreceptor proteins | Hiramatsu 2019 Mol Biol Cell | https://doi.org/10.1091/mbc.e19-08-0434 |
| Mechanistic (mammalian context) | Mammalian EDEM2 has **bona fide mannosidase activity**, weak on free glycans/native glycoproteins but stronger on **denatured/unfolded glycoproteins**; trimming can proceed from **M8 to M5** | In vitro mammalian biochemistry with recombinant proteins and glycan analysis | ERManI trimmed free glycans about **3-fold** more than EDEM1/EDEM2; EDEM2 interacts with **PDI/TXNDC11**, with ~**50% stronger** co-IP with TXNDC11 in excerpt (pqac-00000007, pqac-00000008, pqac-00000009, pqac-00000013) | Provides conserved mechanistic context for Drosophila Edem2: likely a **folding-state-sensitive GH47 α1,2-mannosidase-like ERAD factor** acting preferentially on misfolded glycoproteins | Shenkman 2018 Commun Biol | https://doi.org/10.1038/s42003-018-0174-8 |
| Mechanistic (mammalian context) | Recent synthesis of mammalian work places **EDEM2 at the first mannose-trimming step that initiates gpERAD**, acting with **TXNDC11** before further trimming by other EDEMs | Mammalian ERAD pathway synthesis/review of primary studies | No new kinetic values in excerpt; mechanistic placement cites prior primary studies (pqac-00000012) | Supports inference that Drosophila Edem2 likely functions early in glycoprotein ERAD by generating/advancing the demannosylation signal on terminally misfolded clients | Ninagawa 2024 eLife | https://doi.org/10.1101/2023.10.18.562958 |


*Table: This table compiles the most relevant experimental and mechanistic findings for Drosophila Edem2/CG5682, emphasizing direct Drosophila evidence and clearly separating mammalian EDEM2 context used for functional inference.*