{"gene":"EMC2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2021,"finding":"WNK1 functions as an assembly factor for the human ER membrane protein complex (EMC) by using a conserved amphipathic helix to stabilize the soluble subunit EMC2, binding at the EMC2-8 interface. This interaction shields a hydrophobic surface on EMC2, preventing promiscuous interactions of unassembled EMC2 and directly competing with E3 ubiquitin ligases for binding, thereby permitting proper EMC assembly. Depletion of WNK1 destabilizes both the EMC and its membrane protein clients.","method":"Co-immunoprecipitation, domain mutagenesis, biochemical reconstitution, depletion experiments with functional readout of EMC client stability","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal binding assays, mutagenesis of amphipathic helix, functional client stability readout, multiple orthogonal methods in a single rigorous study","pmids":["33964204"],"is_preprint":false},{"year":2018,"finding":"Yeast Hsp90 physically interacts with Emc2p (the yeast ortholog of EMC2) in co-precipitation experiments, and this interaction occurs regardless of whether Emc2p contains its tetratricopeptide repeat (TPR) motif. Genetic interactions were also demonstrated between EMC2 and the Hsp90 co-chaperone STI1, and yeast lacking multiple EMC subunits show defective folding of the Hsp90 client glucocorticoid receptor.","method":"Co-precipitation of bacterially expressed proteins, yeast genetic epistasis (growth assays with Hsp90 inhibitor, double-mutant analysis), glucocorticoid receptor folding assay","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — physical interaction confirmed by pulldown plus genetic epistasis and functional client-folding assay, single lab","pmids":["29808299"],"is_preprint":false},{"year":2015,"finding":"Knockout of EMC2 (along with EMC3, SEL1L, DERL2, UBE2G2, UBE2J1, and HRD1) confers strong protection against West Nile virus-induced cell death in human cells without blocking WNV replication, placing EMC2 in the ER-associated protein degradation (ERAD) pathway as an essential link between WNV replication and downstream cell death.","method":"Genome-wide CRISPR-Cas9 screen, validation with multiple WNV strains in three cell lines, loss-of-function with cell viability and viral replication readouts","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO validated across multiple cell lines and viral strains, but mechanistic placement relies on pathway membership inference rather than direct biochemical reconstitution","pmids":["26190106"],"is_preprint":false},{"year":2019,"finding":"EMC2 (referred to as TTC35 in this study) is required for efficient flavivirus (DENV, YFV, ZIKV) infection of human cells, acting at or prior to virus uncoating (as shown by a novel uncoating assay measuring host RNA-binding protein interactions with incoming viral RNA), and is also required for viral protein accumulation in cells harboring a ZIKV replicon, indicating a role in viral protein biogenesis.","method":"siRNA depletion, novel uncoating assay, ZIKV replicon system, in vivo mosquito EMC subunit depletion with viral propagation readout","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — two distinct functional assays (uncoating and replicon) in the same study, but mechanistic detail is limited in the abstract","pmids":["31273220"],"is_preprint":false},{"year":2024,"finding":"EMC2 interacts with TFRC (transferrin receptor) and promotes its ubiquitin-proteasomal degradation in nasopharyngeal carcinoma cells. EMC2 knockdown increases TFRC levels, enhancing ferroptosis, while EMC2 overexpression reduces TFRC levels and suppresses ferroptosis, establishing the EMC2-TFRC axis as a ferroptosis regulatory pathway.","method":"Co-immunoprecipitation, quantitative proteomics, protease inhibition assays, ubiquitin detection, rescue experiments, in vitro and in vivo xenograft models","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — physical interaction confirmed by Co-IP, ubiquitination detected, functional rescue performed, single lab","pmids":["39709720"],"is_preprint":false},{"year":2025,"finding":"EMC2 acts as a scaffold protein to recruit the deubiquitinating enzyme USP7 to ENO1, promoting ENO1 deubiquitylation and stabilization, which then activates the downstream B-MYB/PDK1/AKT(T308)/mTOR(S2448) signaling cascade in breast cancer cells.","method":"Co-immunoprecipitation, ubiquitination assays, loss-of-function/overexpression with signaling pathway readouts (phospho-Western), in vitro and in vivo tumor growth assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for complex formation, ubiquitination assay for mechanism, signaling pathway placement, single lab","pmids":["40303285"],"is_preprint":false},{"year":2025,"finding":"EMC2 interacts with HSP90 to protect FDFT1 (farnesyl diphosphate farnesyl transferase 1) from ER-associated degradation (ERAD), thereby sustaining FDFT1 protein quality and correct ER membrane localization. This stabilization of FDFT1 elevates intracellular cholesterol biosynthesis and decreases ferroptosis susceptibility in triple-negative breast cancer cells.","method":"Co-immunoprecipitation (EMC2-HSP90 interaction), EMC2 knockdown/overexpression with FDFT1 protein stability readout, cholesterol measurement, ferroptosis assays in vitro and in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — physical interaction by Co-IP, functional ERAD protection assay, multiple downstream readouts, single lab","pmids":["40931051"],"is_preprint":false},{"year":2024,"finding":"EMC2 participates in the EMC2-SLC25A46-Mic19 axis that regulates ER-mitochondria contacts. EMC2 functions upstream of SLC25A46 and Mic19 in this pathway, as demonstrated by the requirement of this axis for maintaining ER-mitochondrial contact sites in hepatocytes.","method":"Genetic epistasis (Mic19 liver-specific knockout, re-expression rescue), co-immunoprecipitation/interaction studies, ER-mitochondria contact site quantification by electron microscopy","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse liver KO model with rescue, pathway placement established, but EMC2's direct molecular role within the axis is not fully biochemically resolved from the abstract alone","pmids":["38168065"],"is_preprint":false},{"year":2007,"finding":"KIAA0103 (EMC2 alias) interacts with the tumor suppressor RASSF1C and the spliceosome component PRP3 in yeast two-hybrid screens, interactions subsequently confirmed by in vitro pull-down of bacterially expressed proteins, positioning EMC2 as a node in the nuclear interactome.","method":"Yeast two-hybrid screen, in vitro pull-down with bacterially expressed proteins","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pull-down only without reciprocal Co-IP or functional validation; interactions identified in a broad interactome mapping context","pmids":["17335777"],"is_preprint":false},{"year":2025,"finding":"In fission yeast (Schizosaccharomyces pombe), deletion of oca3/emc2 severely impairs oxygen consumption rates (mitochondrial respiration) and quiescence survival. The respiratory defect is rescued synergistically by disruption of ergosterol biosynthesis and treatment with the membrane fluidizing agent tween 20, implicating membrane fluidity and sterol composition in the EMC2-dependent mitochondrial respiration phenotype.","method":"Gene deletion (oca3Δ), Seahorse metabolic analyzer (oxygen consumption rate), genetic epistasis with erg5Δ, pharmacological membrane fluidization","journal":"Yeast (Chichester, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct measurement of oxygen consumption in KO yeast, epistasis with sterol biosynthesis mutant plus pharmacological rescue, ortholog study in fission yeast","pmids":["40085054"],"is_preprint":false},{"year":2025,"finding":"Compromised EMC2 delayed apoptosis during prolonged ER stress (thapsigargin-induced UPR-to-apoptosis transition) in human cells, as revealed by time-resolved photocatalytic proximity labeling of the ER proteome.","method":"Non-genetic ER proximity labeling (CAT-ER iridium photocatalyst), temporal proteomics during thapsigargin-induced UPR/apoptosis, EMC2 loss-of-function with apoptosis kinetics readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 / Weak — novel proteomics method, single finding reported in abstract without detailed mechanistic follow-up on EMC2 specifically","pmids":["40768357"],"is_preprint":false},{"year":2023,"finding":"EMC2 overexpression in liver cancer cells induced ferroptosis through upregulation of reactive oxygen species (ROS) levels and downregulation of glutathione peroxidase (GPX4) in vitro.","method":"EMC2 overexpression in liver cancer cell lines, ROS measurement, GPX4 protein level assay, ferroptosis markers","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression-based functional assay with limited mechanistic detail on how EMC2 connects to ROS/GPX4","pmids":["37693126"],"is_preprint":false}],"current_model":"EMC2 is a soluble cytosolic subunit of the ER membrane protein complex (EMC) that serves as a scaffold in the EMC assembly process — where it is stabilized by the WNK1 assembly factor binding at the EMC2-8 interface — and functions in ER-associated protein biogenesis, membrane protein insertion/ERAD, and ER-mitochondria contact site regulation (via the EMC2-SLC25A46-Mic19 axis); beyond its canonical EMC role, EMC2 acts as a scaffold recruiting USP7 to deubiquitylate and stabilize ENO1, interacts with HSP90 to protect FDFT1 from ERAD, and regulates ferroptosis susceptibility by controlling TFRC protein levels through ubiquitin-proteasomal degradation."},"narrative":{"mechanistic_narrative":"EMC2 is a soluble cytosolic subunit of the ER membrane protein complex (EMC) that contributes to ER-associated protein biogenesis and membrane protein quality control [PMID:33964204, PMID:26190106]. As an unassembled subunit, EMC2 exposes a hydrophobic surface that is shielded by the assembly factor WNK1, which binds at the EMC2-8 interface via a conserved amphipathic helix and directly competes with E3 ubiquitin ligases, so that loss of WNK1 destabilizes both EMC2 and its membrane protein clients [PMID:33964204]. EMC2 physically associates with the Hsp90 chaperone machinery, an interaction conserved from yeast where EMC subunits are required for folding of Hsp90 clients [PMID:29808299]. Through its scaffolding and protein-stabilization activities EMC2 controls the levels of multiple downstream proteins: it recruits the deubiquitinase USP7 to stabilize ENO1 and activate B-MYB/PDK1/AKT/mTOR signaling [PMID:40303285], cooperates with HSP90 to protect FDFT1 from ER-associated degradation and thereby support cholesterol biosynthesis [PMID:40931051], and promotes ubiquitin-proteasomal degradation of the transferrin receptor TFRC [PMID:39709720]. These activities converge on ferroptosis regulation, with EMC2 generally suppressing ferroptosis susceptibility in cancer cells via the FDFT1 and TFRC axes [PMID:39709720, PMID:40931051]. EMC2 also functions in the EMC2-SLC25A46-Mic19 axis that maintains ER-mitochondria contact sites [PMID:38168065], and EMC-dependent ER protein biogenesis is exploited by flaviviruses and links West Nile virus replication to ERAD-mediated cell death [PMID:26190106, PMID:31273220].","teleology":[{"year":2007,"claim":"Early interactome mapping placed EMC2 (KIAA0103) as a candidate node binding nuclear/spliceosomal partners, before its EMC function was recognized.","evidence":"Yeast two-hybrid screen with in vitro pull-down of RASSF1C and PRP3","pmids":["17335777"],"confidence":"Low","gaps":["Pull-down only without reciprocal Co-IP or functional validation","Functional relevance of RASSF1C/PRP3 binding never followed up","No connection to EMC role established"]},{"year":2015,"claim":"A genome-wide screen positioned EMC2 within the ERAD pathway and showed it is required for West Nile virus-induced cell death without affecting replication, indicating a role linking ER protein degradation to downstream death signaling.","evidence":"Genome-wide CRISPR-Cas9 screen validated across multiple WNV strains and cell lines, with viability and replication readouts","pmids":["26190106"],"confidence":"Medium","gaps":["Mechanistic placement inferred from pathway co-membership, not biochemistry","Direct EMC2 substrate in the death pathway unidentified"]},{"year":2018,"claim":"Yeast work connected EMC2 to chaperone-assisted protein folding by demonstrating physical interaction with Hsp90 and functional requirement of EMC subunits for Hsp90 client maturation.","evidence":"Co-precipitation of bacterially expressed proteins, yeast genetic epistasis with STI1, glucocorticoid receptor folding assay","pmids":["29808299"],"confidence":"Medium","gaps":["TPR-independence of binding leaves the interaction interface undefined","Human relevance not directly tested in this study"]},{"year":2019,"claim":"EMC2 was shown to act in flavivirus infection at or before uncoating and in viral protein biogenesis, refining where in the viral life cycle the EMC contributes.","evidence":"siRNA depletion, novel uncoating assay, ZIKV replicon system, in vivo mosquito depletion","pmids":["31273220"],"confidence":"Medium","gaps":["Molecular step EMC2 performs during uncoating not resolved","Whether host or viral membrane proteins are the relevant clients unknown"]},{"year":2021,"claim":"The assembly logic of the EMC was resolved by showing WNK1 chaperones the soluble subunit EMC2, shielding its hydrophobic surface from E3 ligases to permit complex assembly.","evidence":"Co-immunoprecipitation, amphipathic-helix mutagenesis, biochemical reconstitution, depletion with EMC client stability readout","pmids":["33964204"],"confidence":"High","gaps":["Structure of the WNK1-EMC2 complex not solved here","Identity of competing E3 ligases not pinned down"]},{"year":2023,"claim":"EMC2 was first linked to ferroptosis, with overexpression inducing ROS and downregulating GPX4 in liver cancer cells.","evidence":"EMC2 overexpression with ROS, GPX4, and ferroptosis marker readouts","pmids":["37693126"],"confidence":"Low","gaps":["Single-lab overexpression study with limited mechanistic detail","Pathway connecting EMC2 to ROS/GPX4 unresolved","Direction of effect opposite to later studies, not reconciled"]},{"year":2024,"claim":"EMC2 was assigned a direct role in iron handling and ferroptosis by showing it binds TFRC and drives its ubiquitin-proteasomal degradation, with the axis modulating ferroptosis in nasopharyngeal carcinoma.","evidence":"Co-immunoprecipitation, quantitative proteomics, ubiquitination and protease inhibition assays, rescue, xenografts","pmids":["39709720"],"confidence":"Medium","gaps":["E3 ligase mediating TFRC degradation not identified","Whether canonical EMC is involved or EMC2 acts independently unclear"]},{"year":2024,"claim":"EMC2 was placed upstream in the EMC2-SLC25A46-Mic19 axis required to maintain ER-mitochondria contact sites in hepatocytes.","evidence":"Mic19 liver-specific knockout with rescue, interaction studies, EM quantification of contact sites","pmids":["38168065"],"confidence":"Medium","gaps":["EMC2's direct molecular role within the axis not biochemically resolved","Whether contact-site regulation requires the full EMC unknown"]},{"year":2025,"claim":"EMC2 was shown to act as a scaffold recruiting the deubiquitinase USP7 to stabilize ENO1, activating oncogenic B-MYB/PDK1/AKT/mTOR signaling.","evidence":"Co-immunoprecipitation, ubiquitination assays, phospho-Western signaling readouts, in vitro and in vivo tumor growth","pmids":["40303285"],"confidence":"Medium","gaps":["Whether scaffolding is EMC-dependent unknown","Direct USP7 and ENO1 binding surfaces on EMC2 not mapped"]},{"year":2025,"claim":"EMC2 was shown to cooperate with HSP90 to protect FDFT1 from ERAD, sustaining cholesterol synthesis and suppressing ferroptosis, extending its chaperone-linked client-stabilization role to lipid metabolism.","evidence":"Co-immunoprecipitation, knockdown/overexpression with FDFT1 stability, cholesterol and ferroptosis assays in vitro and in vivo","pmids":["40931051"],"confidence":"Medium","gaps":["Mechanism by which EMC2-HSP90 shields FDFT1 from the ERAD machinery not detailed","Generality across cell types beyond TNBC untested"]},{"year":2025,"claim":"Time-resolved ER proteomics implicated EMC2 in the UPR-to-apoptosis transition, with its loss delaying apoptosis during prolonged ER stress.","evidence":"Photocatalytic ER proximity labeling (CAT-ER), temporal proteomics during thapsigargin-induced UPR, EMC2 loss-of-function apoptosis kinetics","pmids":["40768357"],"confidence":"Low","gaps":["Single finding without dedicated mechanistic follow-up on EMC2","How EMC2 influences the apoptotic switch unknown"]},{"year":2025,"claim":"In fission yeast, loss of the EMC2 ortholog impaired mitochondrial respiration and quiescence survival, with rescue by sterol-biosynthesis disruption and membrane fluidization implicating membrane lipid composition in the phenotype.","evidence":"oca3Δ deletion, Seahorse oxygen consumption, epistasis with erg5Δ, pharmacological membrane fluidization","pmids":["40085054"],"confidence":"Medium","gaps":["Mechanistic link between EMC2 and membrane fluidity not defined","Conservation of the respiration phenotype in mammalian cells untested"]},{"year":null,"claim":"How EMC2's canonical EMC scaffolding role mechanistically connects to its EMC-independent client-stabilization activities (USP7-ENO1, HSP90-FDFT1, TFRC) and to ferroptosis remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model distinguishing EMC-bound from free EMC2 functions","Whether ferroptosis-related activities require the intact EMC is unknown","Opposing ferroptosis effects across cancer types not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,6,10]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,6]}],"complexes":["ER membrane protein complex (EMC)"],"partners":["WNK1","HSP90","USP7","TFRC","SLC25A46","RASSF1C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15006","full_name":"ER membrane protein complex subunit 2","aliases":["Tetratricopeptide repeat protein 35","TPR repeat protein 35"],"length_aa":297,"mass_kda":34.8,"function":"Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins (PubMed:29242231, PubMed:29809151, PubMed:30415835, PubMed:32439656, PubMed:32459176, PubMed:33964204). Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues (PubMed:29242231, PubMed:29809151, PubMed:30415835). Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices (PubMed:29809151, PubMed:30415835). It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes (PubMed:29242231, PubMed:29809151). By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors (PubMed:30415835). By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes (Probable)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q15006/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EMC2","classification":"Not Classified","n_dependent_lines":296,"n_total_lines":1208,"dependency_fraction":0.24503311258278146},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000104412","cell_line_id":"CID001790","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"EMC1","stoichiometry":10.0},{"gene":"EMC3","stoichiometry":10.0},{"gene":"EMC7","stoichiometry":10.0},{"gene":"CCDC47","stoichiometry":10.0},{"gene":"EMC4","stoichiometry":10.0},{"gene":"EMC9","stoichiometry":10.0},{"gene":"EMC8","stoichiometry":10.0},{"gene":"COPA","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"EMC10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001790","total_profiled":1310},"omim":[{"mim_id":"607722","title":"ENDOPLASMIC RETICULUM MEMBRANE PROTEIN COMPLEX, SUBUNIT 2; EMC2","url":"https://www.omim.org/entry/607722"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EMC2"},"hgnc":{"alias_symbol":[],"prev_symbol":["KIAA0103","TTC35"]},"alphafold":{"accession":"Q15006","domains":[{"cath_id":"1.25.40","chopping":"1-111","consensus_level":"medium","plddt":94.9634,"start":1,"end":111}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15006","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15006-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15006-F1-predicted_aligned_error_v6.png","plddt_mean":94.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EMC2","jax_strain_url":"https://www.jax.org/strain/search?query=EMC2"},"sequence":{"accession":"Q15006","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15006.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15006/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15006"}},"corpus_meta":[{"pmid":"26190106","id":"PMC_26190106","title":"A CRISPR-Based Screen Identifies 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association study identifies consistent genomic loci for yield and nutritional quality in Ethiopian sorghum landraces.","date":"2026","source":"The plant genome","url":"https://pubmed.ncbi.nlm.nih.gov/41684087","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15415,"output_tokens":3210,"usd":0.047198,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10760,"output_tokens":3961,"usd":0.076412,"stage2_stop_reason":"end_turn"},"total_usd":0.12361,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"WNK1 functions as an assembly factor for the human ER membrane protein complex (EMC) by using a conserved amphipathic helix to stabilize the soluble subunit EMC2, binding at the EMC2-8 interface. This interaction shields a hydrophobic surface on EMC2, preventing promiscuous interactions of unassembled EMC2 and directly competing with E3 ubiquitin ligases for binding, thereby permitting proper EMC assembly. Depletion of WNK1 destabilizes both the EMC and its membrane protein clients.\",\n      \"method\": \"Co-immunoprecipitation, domain mutagenesis, biochemical reconstitution, depletion experiments with functional readout of EMC client stability\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal binding assays, mutagenesis of amphipathic helix, functional client stability readout, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"33964204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Yeast Hsp90 physically interacts with Emc2p (the yeast ortholog of EMC2) in co-precipitation experiments, and this interaction occurs regardless of whether Emc2p contains its tetratricopeptide repeat (TPR) motif. Genetic interactions were also demonstrated between EMC2 and the Hsp90 co-chaperone STI1, and yeast lacking multiple EMC subunits show defective folding of the Hsp90 client glucocorticoid receptor.\",\n      \"method\": \"Co-precipitation of bacterially expressed proteins, yeast genetic epistasis (growth assays with Hsp90 inhibitor, double-mutant analysis), glucocorticoid receptor folding assay\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — physical interaction confirmed by pulldown plus genetic epistasis and functional client-folding assay, single lab\",\n      \"pmids\": [\"29808299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockout of EMC2 (along with EMC3, SEL1L, DERL2, UBE2G2, UBE2J1, and HRD1) confers strong protection against West Nile virus-induced cell death in human cells without blocking WNV replication, placing EMC2 in the ER-associated protein degradation (ERAD) pathway as an essential link between WNV replication and downstream cell death.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, validation with multiple WNV strains in three cell lines, loss-of-function with cell viability and viral replication readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO validated across multiple cell lines and viral strains, but mechanistic placement relies on pathway membership inference rather than direct biochemical reconstitution\",\n      \"pmids\": [\"26190106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EMC2 (referred to as TTC35 in this study) is required for efficient flavivirus (DENV, YFV, ZIKV) infection of human cells, acting at or prior to virus uncoating (as shown by a novel uncoating assay measuring host RNA-binding protein interactions with incoming viral RNA), and is also required for viral protein accumulation in cells harboring a ZIKV replicon, indicating a role in viral protein biogenesis.\",\n      \"method\": \"siRNA depletion, novel uncoating assay, ZIKV replicon system, in vivo mosquito EMC subunit depletion with viral propagation readout\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — two distinct functional assays (uncoating and replicon) in the same study, but mechanistic detail is limited in the abstract\",\n      \"pmids\": [\"31273220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EMC2 interacts with TFRC (transferrin receptor) and promotes its ubiquitin-proteasomal degradation in nasopharyngeal carcinoma cells. EMC2 knockdown increases TFRC levels, enhancing ferroptosis, while EMC2 overexpression reduces TFRC levels and suppresses ferroptosis, establishing the EMC2-TFRC axis as a ferroptosis regulatory pathway.\",\n      \"method\": \"Co-immunoprecipitation, quantitative proteomics, protease inhibition assays, ubiquitin detection, rescue experiments, in vitro and in vivo xenograft models\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — physical interaction confirmed by Co-IP, ubiquitination detected, functional rescue performed, single lab\",\n      \"pmids\": [\"39709720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EMC2 acts as a scaffold protein to recruit the deubiquitinating enzyme USP7 to ENO1, promoting ENO1 deubiquitylation and stabilization, which then activates the downstream B-MYB/PDK1/AKT(T308)/mTOR(S2448) signaling cascade in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, loss-of-function/overexpression with signaling pathway readouts (phospho-Western), in vitro and in vivo tumor growth assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for complex formation, ubiquitination assay for mechanism, signaling pathway placement, single lab\",\n      \"pmids\": [\"40303285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EMC2 interacts with HSP90 to protect FDFT1 (farnesyl diphosphate farnesyl transferase 1) from ER-associated degradation (ERAD), thereby sustaining FDFT1 protein quality and correct ER membrane localization. This stabilization of FDFT1 elevates intracellular cholesterol biosynthesis and decreases ferroptosis susceptibility in triple-negative breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (EMC2-HSP90 interaction), EMC2 knockdown/overexpression with FDFT1 protein stability readout, cholesterol measurement, ferroptosis assays in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — physical interaction by Co-IP, functional ERAD protection assay, multiple downstream readouts, single lab\",\n      \"pmids\": [\"40931051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EMC2 participates in the EMC2-SLC25A46-Mic19 axis that regulates ER-mitochondria contacts. EMC2 functions upstream of SLC25A46 and Mic19 in this pathway, as demonstrated by the requirement of this axis for maintaining ER-mitochondrial contact sites in hepatocytes.\",\n      \"method\": \"Genetic epistasis (Mic19 liver-specific knockout, re-expression rescue), co-immunoprecipitation/interaction studies, ER-mitochondria contact site quantification by electron microscopy\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse liver KO model with rescue, pathway placement established, but EMC2's direct molecular role within the axis is not fully biochemically resolved from the abstract alone\",\n      \"pmids\": [\"38168065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIAA0103 (EMC2 alias) interacts with the tumor suppressor RASSF1C and the spliceosome component PRP3 in yeast two-hybrid screens, interactions subsequently confirmed by in vitro pull-down of bacterially expressed proteins, positioning EMC2 as a node in the nuclear interactome.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro pull-down with bacterially expressed proteins\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pull-down only without reciprocal Co-IP or functional validation; interactions identified in a broad interactome mapping context\",\n      \"pmids\": [\"17335777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In fission yeast (Schizosaccharomyces pombe), deletion of oca3/emc2 severely impairs oxygen consumption rates (mitochondrial respiration) and quiescence survival. The respiratory defect is rescued synergistically by disruption of ergosterol biosynthesis and treatment with the membrane fluidizing agent tween 20, implicating membrane fluidity and sterol composition in the EMC2-dependent mitochondrial respiration phenotype.\",\n      \"method\": \"Gene deletion (oca3Δ), Seahorse metabolic analyzer (oxygen consumption rate), genetic epistasis with erg5Δ, pharmacological membrane fluidization\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct measurement of oxygen consumption in KO yeast, epistasis with sterol biosynthesis mutant plus pharmacological rescue, ortholog study in fission yeast\",\n      \"pmids\": [\"40085054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Compromised EMC2 delayed apoptosis during prolonged ER stress (thapsigargin-induced UPR-to-apoptosis transition) in human cells, as revealed by time-resolved photocatalytic proximity labeling of the ER proteome.\",\n      \"method\": \"Non-genetic ER proximity labeling (CAT-ER iridium photocatalyst), temporal proteomics during thapsigargin-induced UPR/apoptosis, EMC2 loss-of-function with apoptosis kinetics readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — novel proteomics method, single finding reported in abstract without detailed mechanistic follow-up on EMC2 specifically\",\n      \"pmids\": [\"40768357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EMC2 overexpression in liver cancer cells induced ferroptosis through upregulation of reactive oxygen species (ROS) levels and downregulation of glutathione peroxidase (GPX4) in vitro.\",\n      \"method\": \"EMC2 overexpression in liver cancer cell lines, ROS measurement, GPX4 protein level assay, ferroptosis markers\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression-based functional assay with limited mechanistic detail on how EMC2 connects to ROS/GPX4\",\n      \"pmids\": [\"37693126\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EMC2 is a soluble cytosolic subunit of the ER membrane protein complex (EMC) that serves as a scaffold in the EMC assembly process — where it is stabilized by the WNK1 assembly factor binding at the EMC2-8 interface — and functions in ER-associated protein biogenesis, membrane protein insertion/ERAD, and ER-mitochondria contact site regulation (via the EMC2-SLC25A46-Mic19 axis); beyond its canonical EMC role, EMC2 acts as a scaffold recruiting USP7 to deubiquitylate and stabilize ENO1, interacts with HSP90 to protect FDFT1 from ERAD, and regulates ferroptosis susceptibility by controlling TFRC protein levels through ubiquitin-proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EMC2 is a soluble cytosolic subunit of the ER membrane protein complex (EMC) that contributes to ER-associated protein biogenesis and membrane protein quality control [#0, #2]. As an unassembled subunit, EMC2 exposes a hydrophobic surface that is shielded by the assembly factor WNK1, which binds at the EMC2-8 interface via a conserved amphipathic helix and directly competes with E3 ubiquitin ligases, so that loss of WNK1 destabilizes both EMC2 and its membrane protein clients [#0]. EMC2 physically associates with the Hsp90 chaperone machinery, an interaction conserved from yeast where EMC subunits are required for folding of Hsp90 clients [#1]. Through its scaffolding and protein-stabilization activities EMC2 controls the levels of multiple downstream proteins: it recruits the deubiquitinase USP7 to stabilize ENO1 and activate B-MYB/PDK1/AKT/mTOR signaling [#5], cooperates with HSP90 to protect FDFT1 from ER-associated degradation and thereby support cholesterol biosynthesis [#6], and promotes ubiquitin-proteasomal degradation of the transferrin receptor TFRC [#4]. These activities converge on ferroptosis regulation, with EMC2 generally suppressing ferroptosis susceptibility in cancer cells via the FDFT1 and TFRC axes [#4, #6]. EMC2 also functions in the EMC2-SLC25A46-Mic19 axis that maintains ER-mitochondria contact sites [#7], and EMC-dependent ER protein biogenesis is exploited by flaviviruses and links West Nile virus replication to ERAD-mediated cell death [#2, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Early interactome mapping placed EMC2 (KIAA0103) as a candidate node binding nuclear/spliceosomal partners, before its EMC function was recognized.\",\n      \"evidence\": \"Yeast two-hybrid screen with in vitro pull-down of RASSF1C and PRP3\",\n      \"pmids\": [\"17335777\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pull-down only without reciprocal Co-IP or functional validation\", \"Functional relevance of RASSF1C/PRP3 binding never followed up\", \"No connection to EMC role established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A genome-wide screen positioned EMC2 within the ERAD pathway and showed it is required for West Nile virus-induced cell death without affecting replication, indicating a role linking ER protein degradation to downstream death signaling.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen validated across multiple WNV strains and cell lines, with viability and replication readouts\",\n      \"pmids\": [\"26190106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic placement inferred from pathway co-membership, not biochemistry\", \"Direct EMC2 substrate in the death pathway unidentified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Yeast work connected EMC2 to chaperone-assisted protein folding by demonstrating physical interaction with Hsp90 and functional requirement of EMC subunits for Hsp90 client maturation.\",\n      \"evidence\": \"Co-precipitation of bacterially expressed proteins, yeast genetic epistasis with STI1, glucocorticoid receptor folding assay\",\n      \"pmids\": [\"29808299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TPR-independence of binding leaves the interaction interface undefined\", \"Human relevance not directly tested in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"EMC2 was shown to act in flavivirus infection at or before uncoating and in viral protein biogenesis, refining where in the viral life cycle the EMC contributes.\",\n      \"evidence\": \"siRNA depletion, novel uncoating assay, ZIKV replicon system, in vivo mosquito depletion\",\n      \"pmids\": [\"31273220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular step EMC2 performs during uncoating not resolved\", \"Whether host or viral membrane proteins are the relevant clients unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The assembly logic of the EMC was resolved by showing WNK1 chaperones the soluble subunit EMC2, shielding its hydrophobic surface from E3 ligases to permit complex assembly.\",\n      \"evidence\": \"Co-immunoprecipitation, amphipathic-helix mutagenesis, biochemical reconstitution, depletion with EMC client stability readout\",\n      \"pmids\": [\"33964204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the WNK1-EMC2 complex not solved here\", \"Identity of competing E3 ligases not pinned down\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"EMC2 was first linked to ferroptosis, with overexpression inducing ROS and downregulating GPX4 in liver cancer cells.\",\n      \"evidence\": \"EMC2 overexpression with ROS, GPX4, and ferroptosis marker readouts\",\n      \"pmids\": [\"37693126\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab overexpression study with limited mechanistic detail\", \"Pathway connecting EMC2 to ROS/GPX4 unresolved\", \"Direction of effect opposite to later studies, not reconciled\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"EMC2 was assigned a direct role in iron handling and ferroptosis by showing it binds TFRC and drives its ubiquitin-proteasomal degradation, with the axis modulating ferroptosis in nasopharyngeal carcinoma.\",\n      \"evidence\": \"Co-immunoprecipitation, quantitative proteomics, ubiquitination and protease inhibition assays, rescue, xenografts\",\n      \"pmids\": [\"39709720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating TFRC degradation not identified\", \"Whether canonical EMC is involved or EMC2 acts independently unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"EMC2 was placed upstream in the EMC2-SLC25A46-Mic19 axis required to maintain ER-mitochondria contact sites in hepatocytes.\",\n      \"evidence\": \"Mic19 liver-specific knockout with rescue, interaction studies, EM quantification of contact sites\",\n      \"pmids\": [\"38168065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EMC2's direct molecular role within the axis not biochemically resolved\", \"Whether contact-site regulation requires the full EMC unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"EMC2 was shown to act as a scaffold recruiting the deubiquitinase USP7 to stabilize ENO1, activating oncogenic B-MYB/PDK1/AKT/mTOR signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, phospho-Western signaling readouts, in vitro and in vivo tumor growth\",\n      \"pmids\": [\"40303285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether scaffolding is EMC-dependent unknown\", \"Direct USP7 and ENO1 binding surfaces on EMC2 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"EMC2 was shown to cooperate with HSP90 to protect FDFT1 from ERAD, sustaining cholesterol synthesis and suppressing ferroptosis, extending its chaperone-linked client-stabilization role to lipid metabolism.\",\n      \"evidence\": \"Co-immunoprecipitation, knockdown/overexpression with FDFT1 stability, cholesterol and ferroptosis assays in vitro and in vivo\",\n      \"pmids\": [\"40931051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which EMC2-HSP90 shields FDFT1 from the ERAD machinery not detailed\", \"Generality across cell types beyond TNBC untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Time-resolved ER proteomics implicated EMC2 in the UPR-to-apoptosis transition, with its loss delaying apoptosis during prolonged ER stress.\",\n      \"evidence\": \"Photocatalytic ER proximity labeling (CAT-ER), temporal proteomics during thapsigargin-induced UPR, EMC2 loss-of-function apoptosis kinetics\",\n      \"pmids\": [\"40768357\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single finding without dedicated mechanistic follow-up on EMC2\", \"How EMC2 influences the apoptotic switch unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In fission yeast, loss of the EMC2 ortholog impaired mitochondrial respiration and quiescence survival, with rescue by sterol-biosynthesis disruption and membrane fluidization implicating membrane lipid composition in the phenotype.\",\n      \"evidence\": \"oca3Δ deletion, Seahorse oxygen consumption, epistasis with erg5Δ, pharmacological membrane fluidization\",\n      \"pmids\": [\"40085054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between EMC2 and membrane fluidity not defined\", \"Conservation of the respiration phenotype in mammalian cells untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EMC2's canonical EMC scaffolding role mechanistically connects to its EMC-independent client-stabilization activities (USP7-ENO1, HSP90-FDFT1, TFRC) and to ferroptosis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model distinguishing EMC-bound from free EMC2 functions\", \"Whether ferroptosis-related activities require the intact EMC is unknown\", \"Opposing ferroptosis effects across cancer types not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 6, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [\"ER membrane protein complex (EMC)\"],\n    \"partners\": [\"WNK1\", \"HSP90\", \"USP7\", \"TFRC\", \"SLC25A46\", \"RASSF1C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}