| Source | Year | Journal | Experimental system / assays | Enzymatic reaction | Substrate specificity / preferences | Required binding partners | Main mechanistic conclusion | URL | Evidence |
|---|---:|---|---|---|---|---|---|---|---|
| George et al. | 2020 | *eLife* | Human HCT116 cells; EDEM2 knockout/rescue; cycloheximide chase; co-immunoprecipitation; non-reducing SDS-PAGE; purified complex in vitro glycan-trimming assays | Converts **Man9GlcNAc2 (M9)** to **Man8GlcNAc2 isomer B (M8B)**, the first demannosylation step in mammalian glycoprotein ERAD | B-branch-specific removal of the outermost α1,2-linked mannose from M9; acts on ERAD glycoprotein substrates | **TXNDC11 required** via stable intermolecular disulfide bond (**EDEM2 C558–TXNDC11 C692**); **PDI associates** with EDEM2 but TXNDC11 is essential for full activity | Established human EDEM2 as the **initiator mannosidase** of gpERAD; EDEM2 alone is insufficient, but the **EDEM2–TXNDC11 complex** is catalytically active in vitro and required in cells for substrate trimming and degradation | https://doi.org/10.7554/elife.53455 | (pqac-00000001, pqac-00000004, pqac-00000006) |
| Shenkman et al. | 2018 | *Communications Biology* | Human cell-derived immunoprecipitated EDEM2; in vitro glycan trimming; HPLC analysis of free glycans, native glycoproteins, and denatured glycoproteins; co-IP | Demonstrated bona fide α-mannosidase activity of EDEM2 on glycoprotein N-glycans; trimming observed from higher-mannose forms toward **M7–M5** in vitro | Activity is modest on free oligosaccharides and native glycoproteins but **markedly enhanced on denatured/unfolded glycoproteins**; supports preference for misfolded ERAD clients | **TXNDC11 and PDI interact** with EDEM2; oxidoreductases enhance activity on glycoproteins | EDEM2 is a functional ERAD mannosidase whose activity is **folding-state sensitive**, providing a mechanism for preferential targeting of unfolded/misfolded glycoproteins | https://doi.org/10.1038/s42003-018-0174-8 | (pqac-00000002, pqac-00000005) |
| Murase et al. | 2023 | *BPB Reports* | HEK293 cells; ER stress induction (thapsigargin, tunicamycin, brefeldin A); MG132, DTT, cycloheximide; SEL1L- and TXNDC11-deficient cells; immunoblotting/qPCR | Supports EDEM2 as the **earliest ER-resident ERAD mannosidase** in the pathway rather than redefining the catalytic chemistry | Substrates are misfolded **N-glycosylated ER proteins** entering SEL1L-HRD1-dependent ERAD | **TXNDC11 stabilizes EDEM2** and supports its activity; EDEM2 also physically/functionally links to **SEL1L-mediated ERAD** | Recent evidence indicates EDEM2 is **post-transcriptionally regulated**, depends on TXNDC11 for protein stability, and is itself at least partly turned over by **SEL1L-mediated ERAD** | https://doi.org/10.1248/bpbreports.6.6_193 | (pqac-00000003, pqac-00000011, pqac-00000012) |
| Ninagawa et al. | 2024 | *eLife* | Gene-disrupted cells for UGGT1/2, SEL1L, and EDEM family components; degradation assays of ATF6α, NHK, and other ERAD substrates; inhibitor studies (kifunensine, DNJ) | Places EDEM2 at the first mannose-trimming step (**M9→M8B**) within the broader sequential ERAD pathway that competes with UGGT1-mediated reglucosylation | EDEM-dependent pathway acts on **unstable/misfolded glycoproteins** destined for OS9/XTP3B recognition and HRD1-SEL1L delivery | EDEM2 functions as part of the **EDEM2–TXNDC11** initiating step; downstream EDEM1/3 perform further trimming | Current pathway model: glycoprotein fate is a **tug-of-war between UGGT1-mediated refolding cycles and EDEM-driven mannose trimming**; EDEM2 is the entry-point enzyme for degradation-directed trimming | https://doi.org/10.1101/2023.10.18.562958 | (pqac-00000013, pqac-00000014, pqac-00000015, pqac-00000017) |


*Table: This table summarizes primary mechanistic evidence for human EDEM2, including its catalytic reaction, substrate preferences, dependence on TXNDC11 and association with PDI, and the experimental systems used to define its role in glycoprotein ERAD. It is useful for functional annotation because it distinguishes direct biochemical evidence from broader pathway and regulatory studies.*