{"gene":"NOMO2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2004,"finding":"Nicalin and NOMO (Nodal modulator, previously known as pM5) form a protein complex that antagonizes Nodal/TGF-beta signaling. Ectopic expression of both proteins in zebrafish embryos causes cyclopia (a phenotype arising from defects in mesendoderm patterning via the Nodal pathway). Knockdown of NOMO increased anterior axial mesendoderm and enlarged hatching gland. Nodal- and Activin-induced signaling was inhibited by Nicalin and NOMO in a cell-based reporter assay.","method":"Zebrafish ectopic expression, morpholino knockdown, cell-based Nodal/Activin reporter assay, genetic epistasis with Lefty","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vivo gain/loss-of-function in zebrafish, cell-based reporter assay, epistasis with Lefty), replicated across assays in a single study","pmids":["15257293"],"is_preprint":false},{"year":2007,"finding":"Nicalin controls the assembly and stability of the Nicalin-NOMO complex at the endoplasmic reticulum. RNAi knockdown of either Nicalin or NOMO causes instability of the binding partner, indicating mutual stabilization via complex formation. Overexpression of Nicalin increases NOMO levels post-transcriptionally, while Nicalin itself is a limiting factor for assembly. NOMO is produced in excess and either stabilized by Nicalin or rapidly degraded.","method":"RNA interference knockdown, overexpression, Western blot (post-transcriptional regulation), ER localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi and overexpression with post-transcriptional analysis, single lab with two orthogonal approaches","pmids":["17261586"],"is_preprint":false},{"year":2010,"finding":"TMEM147 is a novel ~22 kDa core component of the Nicalin-NOMO complex at the ER, identified by mass spectrometry from affinity-purified complex preparations. Overexpression and knockdown experiments show close interdependence of TMEM147, Nicalin, and NOMO levels, consistent with a shared complex. Assembly is hierarchical, beginning with a Nicalin-NOMO intermediate; Nicalin stabilizes both NOMO and TMEM147 and is the limiting factor regulating assembly rate.","method":"Affinity purification, mass spectrometry, overexpression, RNAi knockdown, Western blot, ER localization, zebrafish expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mass spectrometry identification from purified complex, validated by reciprocal knockdown/overexpression, multiple orthogonal methods in one study","pmids":["20538592"],"is_preprint":false},{"year":2020,"finding":"NOMO is a component of a ~360 kDa ribosome-associated translocon complex comprising Sec61, TMCO1, CCDC47, Nicalin, TMEM147, and NOMO. Cryo-EM reveals this assembly at the ribosome exit tunnel organized around a central membrane cavity. High-throughput mRNA sequencing shows selective engagement of this translocon with hundreds of multi-pass membrane proteins. Cells lacking accessory components including NOMO show reduced levels of the glutamate transporter EAAT1, a multi-pass membrane protein client.","method":"Cryo-electron microscopy, ribosome co-purification, high-throughput mRNA sequencing, genetic knockout with EAAT1 client protein readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation by KO and client protein assay, multiple orthogonal methods","pmids":["32820719"],"is_preprint":false},{"year":2021,"finding":"NOMO1 is required to sustain ER morphology. Overexpression of NOMO1 imposes a sheet morphology on the ER, whereas depletion of NOMO1 and its orthologs causes collapse of ER morphology with formation of membrane-delineated holes positive for the lysosomal marker LAMP1, and strong increases in autophagy markers LC3 and p62/sequestosome 1. In vitro reconstitution reveals a 'beads on a string' structure of consecutive immunoglobulin-like domains; insertion of additional Ig folds correlates with increased ER intermembrane distance. Genetic epistasis with known ER-shaping proteins Atlastin2 and Climp63 places NOMO1 in the functional network of ER-shaping proteins.","method":"Overexpression, siRNA depletion, live-cell imaging, in vitro reconstitution with domain insertion, genetic epistasis with Atlastin2 and Climp63","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution, loss-of-function imaging, domain engineering, genetic epistasis, multiple orthogonal methods in one study","pmids":["34224731"],"is_preprint":false},{"year":2018,"finding":"Loss of the nomo gene in zebrafish (CRISPR/Cas9 knockout targeting the fibronectin type III domain) results in chondrodysplasia. Key genes of cartilage and skeletal development (sox9a, sox9b, dlx1a, dlx2a, osx, col10a1, col11a2) are downregulated in nomo mutants, placing nomo as a positive regulator of chondrogenesis-related gene expression in vivo.","method":"CRISPR/Cas9 knockout in zebrafish, whole-mount in situ hybridization, qRT-PCR, alcian staining","journal":"Current molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined skeletal phenotype and downstream gene expression analysis, single lab","pmids":["30539698"],"is_preprint":false},{"year":2025,"finding":"NOMO is a force-bearing ER-resident transmembrane protein required for muscle differentiation. A critical interface between distal Ig domains enables NOMO to maintain ER morphology and bear mechanical forces. Two independent tension sensors inserted in the luminal domain demonstrate NOMO assemblies experience forces in the single piconewton range, with significant contribution from the identified Ig-domain interface. Mutations affecting this interface and mechanosensitivity fail to restore NOMO's role during myogenesis in C2C12 differentiation, and NOMO depletion impairs nematode motility.","method":"FRET-based tension sensors, Ig-domain interface mutagenesis, C2C12 myogenesis rescue assays, C. elegans motility assay (loss-of-function), live-cell imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution with tension sensors, mutagenesis, rescue assay, and cross-organism functional validation in a single rigorous study","pmids":["40663102"],"is_preprint":false},{"year":2025,"finding":"NOMO silencing by siRNA sensitizes lung cancer cells to chemo- and radiotherapy through caspase-dependent apoptosis. Antibody array analysis after NOMO inhibition revealed increased phosphorylation of checkpoint kinases Chk1 and Chk2, placing NOMO upstream of the Chk2 pathway in modulating chemo- and radioresistance.","method":"siRNA knockdown, cell viability and apoptosis assays, antibody array for phospho-kinase profiling","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, antibody array (semi-quantitative), single siRNA approach without mechanistic rescue","pmids":["41151896"],"is_preprint":false},{"year":2023,"finding":"NOMO2/3 protein levels are downregulated by the anticancer compound Polyphyllin D in triple-negative breast cancer cells at the protein level but not at the mRNA level, suggesting post-translational regulation of NOMO2/3 by PD.","method":"LC-MS/MS proteomics, Western blot, RT-PCR verification","journal":"Applied biochemistry and biotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, proteomics + Western blot, no mechanistic follow-up on pathway placement; finding is correlational","pmids":["37624509"],"is_preprint":false}],"current_model":"NOMO (NOMO2/NOMO1/NOMO3) is a type I ER-resident transmembrane protein that (1) forms a stable complex with Nicalin and TMEM147 at the ER, where Nicalin controls hierarchical assembly and stability of the complex; (2) acts as part of a ~360 kDa multi-pass membrane protein translocon together with Sec61, TMCO1, CCDC47, Nicalin, and TMEM147; (3) antagonizes Nodal/TGF-beta signaling during vertebrate mesendodermal patterning via the Nicalin-NOMO complex; (4) maintains ER sheet morphology through consecutive luminal immunoglobulin-like domains that set intermembrane distance; and (5) functions as a force-bearing mechanical element in the ER required for myogenesis, experiencing piconewton-range forces through a defined interdomain interface."},"narrative":{"mechanistic_narrative":"NOMO2 (Nodal modulator) is a type I ER-resident transmembrane protein that operates within a hierarchically assembled complex with Nicalin and TMEM147, where Nicalin is the limiting factor controlling assembly and mutual stabilization of all three subunits [PMID:17261586, PMID:20538592]. Through this Nicalin-NOMO complex, NOMO antagonizes Nodal/TGF-beta signaling during vertebrate mesendoderm patterning, with combined overexpression in zebrafish producing cyclopia and knockdown expanding anterior axial mesendoderm [PMID:15257293]. Beyond signaling, NOMO is a structural element of a ~360 kDa ribosome-associated translocon assembled around Sec61, TMCO1, CCDC47, Nicalin, and TMEM147 that engages multi-pass membrane protein biogenesis, with loss of NOMO reducing levels of the multi-pass client EAAT1 [PMID:32820719]. Its luminal architecture of consecutive immunoglobulin-like domains forms a 'beads on a string' structure that sets ER intermembrane distance and maintains ER sheet morphology; NOMO depletion collapses ER morphology, generates LAMP1-positive holes, and triggers autophagy markers, placing it in the ER-shaping network alongside Atlastin2 and Climp63 [PMID:34224731]. A critical interface between distal Ig domains allows NOMO to bear single-piconewton-range forces and act as a mechanical element required for myogenesis, with interface mutants failing to rescue C2C12 differentiation [PMID:40663102]. In zebrafish, loss of nomo causes chondrodysplasia with downregulation of cartilage and skeletal developmental genes, identifying NOMO as a positive regulator of chondrogenesis-related transcription in vivo [PMID:30539698].","teleology":[{"year":2004,"claim":"Established the first function for NOMO by showing it partners with Nicalin to antagonize Nodal/TGF-beta signaling, explaining a developmental patterning role that was previously unknown.","evidence":"Zebrafish ectopic expression and morpholino knockdown, cell-based Nodal/Activin reporter assay, epistasis with Lefty","pmids":["15257293"],"confidence":"High","gaps":["Molecular mechanism by which the complex inhibits Nodal signaling not defined","Direct biochemical interaction with pathway receptors not shown"]},{"year":2007,"claim":"Resolved how the Nicalin-NOMO complex is built and maintained, showing Nicalin governs assembly and post-transcriptionally stabilizes NOMO, which is otherwise produced in excess and degraded.","evidence":"RNAi knockdown and overexpression with Western blot analysis of post-transcriptional regulation at the ER","pmids":["17261586"],"confidence":"Medium","gaps":["Degradation pathway for unassembled NOMO not identified","Stoichiometry of the complex not determined"]},{"year":2010,"claim":"Expanded the complex to include TMEM147 as a core component and demonstrated hierarchical assembly beginning with a Nicalin-NOMO intermediate.","evidence":"Affinity purification with mass spectrometry, reciprocal knockdown/overexpression, ER localization","pmids":["20538592"],"confidence":"High","gaps":["Functional contribution of TMEM147 to NOMO activity not dissected","Structural arrangement of the trimeric complex unresolved at this stage"]},{"year":2020,"claim":"Placed NOMO within a defined ~360 kDa translocon and assigned it a role in multi-pass membrane protein biogenesis, moving it from a signaling modulator to a biogenesis machine component.","evidence":"Cryo-EM, ribosome co-purification, high-throughput mRNA sequencing, genetic knockout with EAAT1 client readout","pmids":["32820719"],"confidence":"High","gaps":["Specific catalytic or substrate-handling step performed by NOMO not defined","Client repertoire dependent specifically on NOMO not fully mapped"]},{"year":2021,"claim":"Defined the structural basis by which NOMO maintains ER morphology, showing its luminal Ig-domain array sets intermembrane distance and that depletion collapses ER sheets and triggers autophagy.","evidence":"Overexpression, siRNA depletion, live-cell imaging, in vitro reconstitution with domain insertion, epistasis with Atlastin2 and Climp63","pmids":["34224731"],"confidence":"High","gaps":["Whether ER-shaping and translocon roles are coupled or separable not resolved","Mechanism linking ER collapse to autophagy induction unknown"]},{"year":2018,"claim":"Connected NOMO to skeletal development in vivo, showing it positively regulates chondrogenesis-related gene expression and is required to prevent chondrodysplasia.","evidence":"CRISPR/Cas9 knockout in zebrafish, whole-mount in situ hybridization, qRT-PCR, alcian staining","pmids":["30539698"],"confidence":"Medium","gaps":["Mechanism linking NOMO loss to downregulation of sox9/dlx/col genes not established","Whether this reflects the Nodal, translocon, or ER-shaping role unclear"]},{"year":2025,"claim":"Demonstrated that NOMO is a mechanical force-bearing element of the ER, identifying an Ig-domain interface that bears piconewton forces and is required for myogenesis across species.","evidence":"FRET-based tension sensors, Ig-domain interface mutagenesis, C2C12 myogenesis rescue, C. elegans motility loss-of-function","pmids":["40663102"],"confidence":"High","gaps":["Source and direction of the forces NOMO bears not fully defined","How mechanosensing feeds into muscle differentiation signaling unknown"]},{"year":2025,"claim":"Began linking NOMO to cancer therapy resistance by placing it upstream of Chk2-pathway activation and apoptosis sensitization in lung cancer cells.","evidence":"siRNA knockdown, viability and apoptosis assays, antibody array for phospho-kinase profiling","pmids":["41151896"],"confidence":"Low","gaps":["Single siRNA approach without mechanistic rescue","Direct link between NOMO and Chk1/Chk2 phosphorylation not established","Semi-quantitative antibody array readout"]},{"year":null,"claim":"How NOMO's distinct activities—Nodal antagonism, translocon participation, ER shaping, and mechanosensing—are integrated or specified in different tissues remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["Whether one structural property underlies all functions or they are separable is unknown","Tissue-specific partner requirements not defined","Functional distinctions among NOMO1/2/3 paralogs not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,6]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,2,3,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,5,6]}],"complexes":["Nicalin-NOMO-TMEM147 complex","Sec61/TMCO1/CCDC47/Nicalin/TMEM147/NOMO multi-pass translocon"],"partners":["NCLN","TMEM147","SEC61","TMCO1","CCDC47"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5JPE7","full_name":"BOS complex subunit NOMO2","aliases":["Nodal modulator 2","pM5 protein 2"],"length_aa":1267,"mass_kda":139.4,"function":"Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes (PubMed:32820719, PubMed:36261522). The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions (PubMed:36261522)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q5JPE7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NOMO2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1165,"dependency_fraction":0.002575107296137339},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NOMO2","total_profiled":1310},"omim":[{"mim_id":"613585","title":"TRANSMEMBRANE PROTEIN 147; TMEM147","url":"https://www.omim.org/entry/613585"},{"mim_id":"609158","title":"NODAL MODULATOR 2; NOMO2","url":"https://www.omim.org/entry/609158"},{"mim_id":"609156","title":"NICALIN; NCLN","url":"https://www.omim.org/entry/609156"}],"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/NOMO2"},"hgnc":{"alias_symbol":["NOMO","PM5"],"prev_symbol":[]},"alphafold":{"accession":"Q5JPE7","domains":[{"cath_id":"2.60.40.10","chopping":"33-121","consensus_level":"medium","plddt":86.5493,"start":33,"end":121},{"cath_id":"2.60.40.10","chopping":"128-215","consensus_level":"medium","plddt":91.4943,"start":128,"end":215},{"cath_id":"2.60.40.10","chopping":"218-327","consensus_level":"medium","plddt":85.2168,"start":218,"end":327},{"cath_id":"2.60.40.1120","chopping":"333-407","consensus_level":"high","plddt":79.6043,"start":333,"end":407},{"cath_id":"2.60.40,2.60.40","chopping":"415-502","consensus_level":"high","plddt":76.5289,"start":415,"end":502},{"cath_id":"2.60.40,2.60.40","chopping":"506-583","consensus_level":"high","plddt":82.9135,"start":506,"end":583},{"cath_id":"2.60.40.1120","chopping":"591-662","consensus_level":"high","plddt":77.704,"start":591,"end":662},{"cath_id":"2.60.40,2.60.40","chopping":"666-705_746-799","consensus_level":"medium","plddt":84.0989,"start":666,"end":799},{"cath_id":"2.60.40.1140","chopping":"801-874","consensus_level":"high","plddt":84.0261,"start":801,"end":874},{"cath_id":"2.60.40.1120","chopping":"1057-1150","consensus_level":"high","plddt":89.5785,"start":1057,"end":1150}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JPE7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JPE7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JPE7-F1-predicted_aligned_error_v6.png","plddt_mean":79.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NOMO2","jax_strain_url":"https://www.jax.org/strain/search?query=NOMO2"},"sequence":{"accession":"Q5JPE7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5JPE7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5JPE7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JPE7"}},"corpus_meta":[{"pmid":"10942240","id":"PMC_10942240","title":"Calicheamicin-conjugated 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Ectopic expression of both proteins in zebrafish embryos causes cyclopia (a phenotype arising from defects in mesendoderm patterning via the Nodal pathway). Knockdown of NOMO increased anterior axial mesendoderm and enlarged hatching gland. Nodal- and Activin-induced signaling was inhibited by Nicalin and NOMO in a cell-based reporter assay.\",\n      \"method\": \"Zebrafish ectopic expression, morpholino knockdown, cell-based Nodal/Activin reporter assay, genetic epistasis with Lefty\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vivo gain/loss-of-function in zebrafish, cell-based reporter assay, epistasis with Lefty), replicated across assays in a single study\",\n      \"pmids\": [\"15257293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Nicalin controls the assembly and stability of the Nicalin-NOMO complex at the endoplasmic reticulum. RNAi knockdown of either Nicalin or NOMO causes instability of the binding partner, indicating mutual stabilization via complex formation. Overexpression of Nicalin increases NOMO levels post-transcriptionally, while Nicalin itself is a limiting factor for assembly. NOMO is produced in excess and either stabilized by Nicalin or rapidly degraded.\",\n      \"method\": \"RNA interference knockdown, overexpression, Western blot (post-transcriptional regulation), ER localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi and overexpression with post-transcriptional analysis, single lab with two orthogonal approaches\",\n      \"pmids\": [\"17261586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TMEM147 is a novel ~22 kDa core component of the Nicalin-NOMO complex at the ER, identified by mass spectrometry from affinity-purified complex preparations. Overexpression and knockdown experiments show close interdependence of TMEM147, Nicalin, and NOMO levels, consistent with a shared complex. Assembly is hierarchical, beginning with a Nicalin-NOMO intermediate; Nicalin stabilizes both NOMO and TMEM147 and is the limiting factor regulating assembly rate.\",\n      \"method\": \"Affinity purification, mass spectrometry, overexpression, RNAi knockdown, Western blot, ER localization, zebrafish expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mass spectrometry identification from purified complex, validated by reciprocal knockdown/overexpression, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20538592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NOMO is a component of a ~360 kDa ribosome-associated translocon complex comprising Sec61, TMCO1, CCDC47, Nicalin, TMEM147, and NOMO. Cryo-EM reveals this assembly at the ribosome exit tunnel organized around a central membrane cavity. High-throughput mRNA sequencing shows selective engagement of this translocon with hundreds of multi-pass membrane proteins. Cells lacking accessory components including NOMO show reduced levels of the glutamate transporter EAAT1, a multi-pass membrane protein client.\",\n      \"method\": \"Cryo-electron microscopy, ribosome co-purification, high-throughput mRNA sequencing, genetic knockout with EAAT1 client protein readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation by KO and client protein assay, multiple orthogonal methods\",\n      \"pmids\": [\"32820719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NOMO1 is required to sustain ER morphology. Overexpression of NOMO1 imposes a sheet morphology on the ER, whereas depletion of NOMO1 and its orthologs causes collapse of ER morphology with formation of membrane-delineated holes positive for the lysosomal marker LAMP1, and strong increases in autophagy markers LC3 and p62/sequestosome 1. In vitro reconstitution reveals a 'beads on a string' structure of consecutive immunoglobulin-like domains; insertion of additional Ig folds correlates with increased ER intermembrane distance. Genetic epistasis with known ER-shaping proteins Atlastin2 and Climp63 places NOMO1 in the functional network of ER-shaping proteins.\",\n      \"method\": \"Overexpression, siRNA depletion, live-cell imaging, in vitro reconstitution with domain insertion, genetic epistasis with Atlastin2 and Climp63\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution, loss-of-function imaging, domain engineering, genetic epistasis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"34224731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of the nomo gene in zebrafish (CRISPR/Cas9 knockout targeting the fibronectin type III domain) results in chondrodysplasia. Key genes of cartilage and skeletal development (sox9a, sox9b, dlx1a, dlx2a, osx, col10a1, col11a2) are downregulated in nomo mutants, placing nomo as a positive regulator of chondrogenesis-related gene expression in vivo.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish, whole-mount in situ hybridization, qRT-PCR, alcian staining\",\n      \"journal\": \"Current molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined skeletal phenotype and downstream gene expression analysis, single lab\",\n      \"pmids\": [\"30539698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NOMO is a force-bearing ER-resident transmembrane protein required for muscle differentiation. A critical interface between distal Ig domains enables NOMO to maintain ER morphology and bear mechanical forces. Two independent tension sensors inserted in the luminal domain demonstrate NOMO assemblies experience forces in the single piconewton range, with significant contribution from the identified Ig-domain interface. Mutations affecting this interface and mechanosensitivity fail to restore NOMO's role during myogenesis in C2C12 differentiation, and NOMO depletion impairs nematode motility.\",\n      \"method\": \"FRET-based tension sensors, Ig-domain interface mutagenesis, C2C12 myogenesis rescue assays, C. elegans motility assay (loss-of-function), live-cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution with tension sensors, mutagenesis, rescue assay, and cross-organism functional validation in a single rigorous study\",\n      \"pmids\": [\"40663102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NOMO silencing by siRNA sensitizes lung cancer cells to chemo- and radiotherapy through caspase-dependent apoptosis. Antibody array analysis after NOMO inhibition revealed increased phosphorylation of checkpoint kinases Chk1 and Chk2, placing NOMO upstream of the Chk2 pathway in modulating chemo- and radioresistance.\",\n      \"method\": \"siRNA knockdown, cell viability and apoptosis assays, antibody array for phospho-kinase profiling\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, antibody array (semi-quantitative), single siRNA approach without mechanistic rescue\",\n      \"pmids\": [\"41151896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NOMO2/3 protein levels are downregulated by the anticancer compound Polyphyllin D in triple-negative breast cancer cells at the protein level but not at the mRNA level, suggesting post-translational regulation of NOMO2/3 by PD.\",\n      \"method\": \"LC-MS/MS proteomics, Western blot, RT-PCR verification\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, proteomics + Western blot, no mechanistic follow-up on pathway placement; finding is correlational\",\n      \"pmids\": [\"37624509\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NOMO (NOMO2/NOMO1/NOMO3) is a type I ER-resident transmembrane protein that (1) forms a stable complex with Nicalin and TMEM147 at the ER, where Nicalin controls hierarchical assembly and stability of the complex; (2) acts as part of a ~360 kDa multi-pass membrane protein translocon together with Sec61, TMCO1, CCDC47, Nicalin, and TMEM147; (3) antagonizes Nodal/TGF-beta signaling during vertebrate mesendodermal patterning via the Nicalin-NOMO complex; (4) maintains ER sheet morphology through consecutive luminal immunoglobulin-like domains that set intermembrane distance; and (5) functions as a force-bearing mechanical element in the ER required for myogenesis, experiencing piconewton-range forces through a defined interdomain interface.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NOMO2 (Nodal modulator) is a type I ER-resident transmembrane protein that operates within a hierarchically assembled complex with Nicalin and TMEM147, where Nicalin is the limiting factor controlling assembly and mutual stabilization of all three subunits [#1, #2]. Through this Nicalin-NOMO complex, NOMO antagonizes Nodal/TGF-beta signaling during vertebrate mesendoderm patterning, with combined overexpression in zebrafish producing cyclopia and knockdown expanding anterior axial mesendoderm [#0]. Beyond signaling, NOMO is a structural element of a ~360 kDa ribosome-associated translocon assembled around Sec61, TMCO1, CCDC47, Nicalin, and TMEM147 that engages multi-pass membrane protein biogenesis, with loss of NOMO reducing levels of the multi-pass client EAAT1 [#3]. Its luminal architecture of consecutive immunoglobulin-like domains forms a 'beads on a string' structure that sets ER intermembrane distance and maintains ER sheet morphology; NOMO depletion collapses ER morphology, generates LAMP1-positive holes, and triggers autophagy markers, placing it in the ER-shaping network alongside Atlastin2 and Climp63 [#4]. A critical interface between distal Ig domains allows NOMO to bear single-piconewton-range forces and act as a mechanical element required for myogenesis, with interface mutants failing to rescue C2C12 differentiation [#6]. In zebrafish, loss of nomo causes chondrodysplasia with downregulation of cartilage and skeletal developmental genes, identifying NOMO as a positive regulator of chondrogenesis-related transcription in vivo [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the first function for NOMO by showing it partners with Nicalin to antagonize Nodal/TGF-beta signaling, explaining a developmental patterning role that was previously unknown.\",\n      \"evidence\": \"Zebrafish ectopic expression and morpholino knockdown, cell-based Nodal/Activin reporter assay, epistasis with Lefty\",\n      \"pmids\": [\"15257293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which the complex inhibits Nodal signaling not defined\", \"Direct biochemical interaction with pathway receptors not shown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved how the Nicalin-NOMO complex is built and maintained, showing Nicalin governs assembly and post-transcriptionally stabilizes NOMO, which is otherwise produced in excess and degraded.\",\n      \"evidence\": \"RNAi knockdown and overexpression with Western blot analysis of post-transcriptional regulation at the ER\",\n      \"pmids\": [\"17261586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation pathway for unassembled NOMO not identified\", \"Stoichiometry of the complex not determined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Expanded the complex to include TMEM147 as a core component and demonstrated hierarchical assembly beginning with a Nicalin-NOMO intermediate.\",\n      \"evidence\": \"Affinity purification with mass spectrometry, reciprocal knockdown/overexpression, ER localization\",\n      \"pmids\": [\"20538592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contribution of TMEM147 to NOMO activity not dissected\", \"Structural arrangement of the trimeric complex unresolved at this stage\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed NOMO within a defined ~360 kDa translocon and assigned it a role in multi-pass membrane protein biogenesis, moving it from a signaling modulator to a biogenesis machine component.\",\n      \"evidence\": \"Cryo-EM, ribosome co-purification, high-throughput mRNA sequencing, genetic knockout with EAAT1 client readout\",\n      \"pmids\": [\"32820719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific catalytic or substrate-handling step performed by NOMO not defined\", \"Client repertoire dependent specifically on NOMO not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the structural basis by which NOMO maintains ER morphology, showing its luminal Ig-domain array sets intermembrane distance and that depletion collapses ER sheets and triggers autophagy.\",\n      \"evidence\": \"Overexpression, siRNA depletion, live-cell imaging, in vitro reconstitution with domain insertion, epistasis with Atlastin2 and Climp63\",\n      \"pmids\": [\"34224731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ER-shaping and translocon roles are coupled or separable not resolved\", \"Mechanism linking ER collapse to autophagy induction unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected NOMO to skeletal development in vivo, showing it positively regulates chondrogenesis-related gene expression and is required to prevent chondrodysplasia.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in zebrafish, whole-mount in situ hybridization, qRT-PCR, alcian staining\",\n      \"pmids\": [\"30539698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking NOMO loss to downregulation of sox9/dlx/col genes not established\", \"Whether this reflects the Nodal, translocon, or ER-shaping role unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that NOMO is a mechanical force-bearing element of the ER, identifying an Ig-domain interface that bears piconewton forces and is required for myogenesis across species.\",\n      \"evidence\": \"FRET-based tension sensors, Ig-domain interface mutagenesis, C2C12 myogenesis rescue, C. elegans motility loss-of-function\",\n      \"pmids\": [\"40663102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source and direction of the forces NOMO bears not fully defined\", \"How mechanosensing feeds into muscle differentiation signaling unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Began linking NOMO to cancer therapy resistance by placing it upstream of Chk2-pathway activation and apoptosis sensitization in lung cancer cells.\",\n      \"evidence\": \"siRNA knockdown, viability and apoptosis assays, antibody array for phospho-kinase profiling\",\n      \"pmids\": [\"41151896\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single siRNA approach without mechanistic rescue\", \"Direct link between NOMO and Chk1/Chk2 phosphorylation not established\", \"Semi-quantitative antibody array readout\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NOMO's distinct activities—Nodal antagonism, translocon participation, ER shaping, and mechanosensing—are integrated or specified in different tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether one structural property underlies all functions or they are separable is unknown\", \"Tissue-specific partner requirements not defined\", \"Functional distinctions among NOMO1/2/3 paralogs not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 2, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 5, 6]}\n    ],\n    \"complexes\": [\n      \"Nicalin-NOMO-TMEM147 complex\",\n      \"Sec61/TMCO1/CCDC47/Nicalin/TMEM147/NOMO multi-pass translocon\"\n    ],\n    \"partners\": [\n      \"NCLN\",\n      \"TMEM147\",\n      \"SEC61\",\n      \"TMCO1\",\n      \"CCDC47\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}