{"gene":"MOAP1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2005,"finding":"RASSF1A directly interacts with MOAP-1, and this interaction is enhanced by activated K-Ras. RASSF1A activates Bax via MOAP-1, and activated K-Ras, RASSF1A, and MOAP-1 synergize to induce Bax activation and cell death. A tumor-derived point mutant of RASSF1A was defective for MOAP-1 interaction and Bax activation. Inhibition of RASSF1A by shRNA impaired K-Ras-mediated Bax activation.","method":"Co-immunoprecipitation, shRNA knockdown, cell death assays, point mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, shRNA, point mutant, multiple orthogonal methods; independently replicated in subsequent studies","pmids":["16344548"],"is_preprint":false},{"year":2007,"finding":"MOAP-1 is a short-lived protein (t½ ~25 min) constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP-1 by inhibiting its polyubiquitination. Elevated MOAP-1 sensitizes cells to apoptosis and promotes recombinant Bax-mediated cytochrome c release from isolated mitochondria. MOAP-1-depleted mitochondria become resistant to Bax-mediated cytochrome c release, and this resistance is restored by in vitro-translated MOAP-1.","method":"Cycloheximide chase, ubiquitination assay, isolated mitochondria cytochrome c release reconstitution with in vitro-translated protein","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with isolated mitochondria and in vitro-translated MOAP-1, multiple orthogonal methods, replicated across labs","pmids":["17535899"],"is_preprint":false},{"year":2008,"finding":"TRIM39 is a MOAP-1-binding protein that extends MOAP-1 half-life by inhibiting its polyubiquitination process. TRIM39 elevates MOAP-1 levels in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. TRIM39 knockdown reduces sensitivity to etoposide-induced apoptosis.","method":"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, siRNA knockdown, isolated mitochondria cytochrome c release assay","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, functional mitochondrial reconstitution, siRNA; replicated and extended in 2012 paper","pmids":["19100260"],"is_preprint":false},{"year":2012,"finding":"MOAP-1 is a substrate of the APC/C(Cdh1) ubiquitin ligase. TRIM39 (a RING domain E3 ligase) stabilizes MOAP-1 by directly inhibiting APC/C(Cdh1)-mediated ubiquitylation. Cdh1 knockdown stabilized MOAP-1, enhancing etoposide-induced Bax activation and apoptosis.","method":"In vitro ubiquitylation assay, siRNA knockdown of Cdh1, immunoprecipitation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitylation assay, siRNA epistasis, multiple orthogonal methods in one rigorous study","pmids":["22529100"],"is_preprint":false},{"year":2016,"finding":"MOAP-1 deficiency in mice confers resistance to Fas-induced hepatocellular apoptosis and lethality. MOAP-1 interacts with MTCH2 at the outer mitochondrial membrane (OMM), and this interaction is required for MTCH2 to engage tBid. In the absence of MOAP-1, mitochondrial accumulation of tBid is markedly impaired, establishing that MOAP-1 facilitates Fas apoptotic signaling by promoting MTCH2-mediated tBid recruitment to mitochondria.","method":"MOAP-1-deficient mouse model, Co-immunoprecipitation, Fas-induced apoptosis assay, tBid mitochondrial accumulation analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout mouse model with defined phenotype, Co-IP identifying MTCH2 interaction, mechanistic tBid recruitment assay, multiple orthogonal methods","pmids":["27320914"],"is_preprint":false},{"year":2016,"finding":"UBR5 (a HECT-family E3 ubiquitin ligase) physically interacts with MOAP-1 and ubiquitylates MOAP-1 in vitro, inhibiting MOAP-1 stability in cells. Dyrk2 kinase, a UBR5 interactor, cooperates with UBR5 in mediating MOAP-1 ubiquitylation. UBR5 knockdown increased MOAP-1 expression, enhanced Bax activation, and sensitized cisplatin-resistant ovarian cancer cells to apoptosis.","method":"Co-immunoprecipitation, in vitro ubiquitylation assay, siRNA knockdown, Bax activation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitylation assay plus Co-IP plus siRNA functional rescue, multiple orthogonal methods in one study","pmids":["27721409"],"is_preprint":false},{"year":2018,"finding":"RACK1 associates with MOAP-1 via electrostatic interactions and recruits the E3 ligase TRAF2 to MOAP-1, resulting in K63-linked ubiquitination of MOAP-1. RACK1 was identified as a robust MOAP-1-interacting protein, linking scaffolding-mediated regulation to MOAP-1 ubiquitination.","method":"Co-immunoprecipitation, ubiquitination assay (K63-linkage specificity), protein interaction mapping","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay identifying K63 linkage, single lab, two orthogonal methods","pmids":["29470995"],"is_preprint":false},{"year":2021,"finding":"MOAP1 binds LC3 via an LC3-interacting region (LIR) motif at its N-terminal region, and this binding is required for efficient phagophore closure during starvation-induced autophagy. MOAP1-deficient cells are hypersensitive to starvation-induced cell death and exhibit predominantly unclosed phagophores. Re-expression of MOAP1, but not its LC3-binding defective mutant (MOAP1-LIR), restored EBSS-induced autophagy.","method":"MOAP1 knockout cells, Halo-tagged LC3 autophagosome completion assay, proteinase K protection assay, Co-immunoprecipitation, LIR mutant rescue","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout, LIR mutant rescue, autophagosome closure assay, proteinase K protection, multiple orthogonal methods in one rigorous study","pmids":["33783314"],"is_preprint":false},{"year":2021,"finding":"X-ray crystal structures of a stably folded domain of MOAP1 reveal high structural similarity to the C-terminal capsid (CA) domain of retroviral Gag proteins, classifying MOAP1 as a domesticated Gag protein derived from ancient retrovirus/retrotransposon integration.","method":"X-ray crystallography","journal":"Proteins","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with structural comparison; single lab but direct structural evidence","pmids":["34357660"],"is_preprint":false},{"year":2025,"finding":"PNMA4 (MOAP1) self-assembles into capsid-like structures that exit human cells. Large PNMA4 particles were observed in mouse male gonadal tissue containing RNA, consistent with capsid formation. Pnma4 knockout mice become prematurely subfertile by six months with drops in sex hormone levels, gonadal atrophy, and abdominal obesity.","method":"Pnma4 knockout mouse model, electron microscopy/particle analysis, RNA-containing particle detection, reproductive phenotype characterization","journal":"Nature aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined reproductive phenotype, capsid-like particle observation, single lab","pmids":["40263616"],"is_preprint":false},{"year":2025,"finding":"PNMA4/MOAP1 is a mitochondrial protein that interacts with MAVS (identified by proximity-based labeling). PNMA4 enhances the interaction between RIG-I and MAVS after RNA virus infection and facilitates K63-linked polyubiquitination of RIG-I at lysine 657 by TRIM25. Pnma4 knockout mice are more susceptible to RNA virus infection, and PNMA4 deficiency reduces RNA virus-induced activation of antiviral (IFN-β) pathways.","method":"Proximity-based labeling (BioID), Co-immunoprecipitation, Pnma4 knockout mouse model, ubiquitination assay (K63-linkage at K657)","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling, Co-IP, KO mouse with viral susceptibility phenotype, ubiquitination assay; single lab","pmids":["40929959"],"is_preprint":false},{"year":2012,"finding":"Influenza A virus PB1-F2 protein specifically interacts with human MOAP-1, as demonstrated by yeast two-hybrid, GST pull-down, and Co-IP assays. PB1-F2 upregulates exogenous MOAP-1 protein levels.","method":"Yeast two-hybrid, GST pull-down, Co-immunoprecipitation, Western blot","journal":"Wei sheng wu xue bao = Acta microbiologica Sinica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — multiple binding assays but no functional mechanistic follow-up, single lab","pmids":["23236846"],"is_preprint":false},{"year":2015,"finding":"MOAP-1 overexpression in cancer cell lines reduces tumorigenesis and upregulates genes in apoptosis (p53, Fas, MST1), DNA damage control (PARP, ATM), and cell metabolism (IR-α, IR-β, AMPK), and stabilizes microtubules. Rapid proteasomal degradation of MOAP-1 can be reversed by the proteasome inhibitor MG132.","method":"Overexpression, xenograft assay, proliferation assay, DNA microarray, proteasome inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with xenograft and microarray, multiple methods; single lab","pmids":["26269600"],"is_preprint":false},{"year":2020,"finding":"The BH3L domain of MOAP-1 is required for its pro-apoptotic activity. A BH3L-deletion mutant (MOAP-1ΔBHB3L) inhibited the apoptotic activity of the MOAP-1/Bax/RASSF1A tricistronic construct and conferred chemo-drug resistance in stable clones, whereas wild-type MOAP-1 in the tricistronic construct promoted dose-dependent apoptosis and chemo-sensitization.","method":"Domain deletion mutagenesis, tricistronic expression construct, cell viability assay, Annexin-V staining, mouse xenograft","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with functional readout in multiple cell models including xenograft; single lab","pmids":["32377840"],"is_preprint":false}],"current_model":"MOAP1 (PNMA4) is a short-lived outer mitochondrial membrane protein, constitutively degraded by the ubiquitin-proteasome system via APC/C(Cdh1) and UBR5, that upon apoptotic stabilization binds and activates BAX to promote cytochrome c release; it functions downstream of the RASSF1A–K-Ras axis, facilitates Fas-induced apoptosis by promoting MTCH2-mediated tBid recruitment to mitochondria, participates in starvation-induced autophagy by binding LC3 via an N-terminal LIR motif to promote phagophore closure, enhances antiviral RIG-I/MAVS signaling by facilitating TRIM25-mediated K63-ubiquitination of RIG-I, and self-assembles into capsid-like structures (reflecting its domesticated retroviral Gag origin) required for reproductive capacity in mice."},"narrative":{"mechanistic_narrative":"MOAP1 (PNMA4) is a short-lived outer mitochondrial membrane protein that functions as a rheostat for apoptotic commitment, acting at the convergence of multiple death signals to drive BAX-dependent mitochondrial outer membrane permeabilization [PMID:17535899, PMID:16344548]. Under basal conditions it is held at low abundance by constitutive ubiquitin-proteasome turnover (t½ ~25 min), and apoptotic stimuli stabilize the protein by inhibiting its polyubiquitination, allowing it to promote BAX-mediated cytochrome c release from mitochondria [PMID:17535899]. Its degradation is controlled by a layered set of ubiquitin ligases: the APC/C(Cdh1) complex and the HECT ligase UBR5 (cooperating with DYRK2) target MOAP1 for destruction, while the RING ligase TRIM39 stabilizes it by antagonizing APC/C(Cdh1)-mediated ubiquitylation, and depleting the destabilizing ligases enhances BAX activation and chemosensitizes cancer cells [PMID:22529100, PMID:27721409, PMID:19100260]. MOAP1 acts downstream of a RASSF1A–K-Ras axis, where activated K-Ras enhances RASSF1A binding to MOAP1 to synergistically activate BAX and induce death [PMID:16344548], and its pro-apoptotic output depends on a BH3-like (BH3L) domain [PMID:32377840]. In Fas-induced hepatocyte apoptosis it operates by binding MTCH2 at the outer mitochondrial membrane to enable MTCH2-dependent recruitment of tBid to mitochondria [PMID:27320914]. Beyond apoptosis, MOAP1 binds LC3 through an N-terminal LIR motif to promote phagophore closure during starvation-induced autophagy [PMID:33783314], and at the mitochondrion it interacts with MAVS to enhance RIG-I/MAVS antiviral signaling by facilitating TRIM25-mediated K63-ubiquitination of RIG-I [PMID:40929959]. Structurally, MOAP1 contains a folded domain resembling the retroviral Gag capsid domain and self-assembles into RNA-containing capsid-like particles, with loss of the gene causing premature subfertility and gonadal atrophy in mice, identifying it as a domesticated Gag protein with a role in reproductive capacity [PMID:34357660, PMID:40263616].","teleology":[{"year":2005,"claim":"Established MOAP1 as the effector linking the RASSF1A–K-Ras tumor-suppressor axis to BAX activation, answering how this signaling module triggers apoptosis.","evidence":"Co-IP, shRNA knockdown, point-mutant analysis, and cell death assays in human cells","pmids":["16344548"],"confidence":"High","gaps":["Did not define the biochemical mechanism by which MOAP1 activates BAX","Did not address how MOAP1 abundance is controlled"]},{"year":2007,"claim":"Showed MOAP1 is a constitutively degraded, short-lived protein stabilized by apoptotic stimuli, defining abundance control as the switch governing its pro-apoptotic activity at mitochondria.","evidence":"Cycloheximide chase, ubiquitination assay, and isolated-mitochondria cytochrome c release reconstitution with in vitro-translated protein","pmids":["17535899"],"confidence":"High","gaps":["The ubiquitin ligase responsible for basal turnover was not identified","The molecular interface with BAX was not resolved"]},{"year":2008,"claim":"Identified TRIM39 as a stabilizing partner that extends MOAP1 half-life, providing the first positive regulator of MOAP1 abundance.","evidence":"Co-IP, ubiquitination assay, cycloheximide chase, siRNA, and isolated-mitochondria cytochrome c release assay","pmids":["19100260"],"confidence":"High","gaps":["The destabilizing ligase that TRIM39 antagonizes was not yet known","Mechanism of TRIM39 inhibition of ubiquitylation undefined"]},{"year":2012,"claim":"Defined APC/C(Cdh1) as the E3 ligase that degrades MOAP1 and showed TRIM39 stabilizes MOAP1 by directly inhibiting this ligase, resolving the regulatory circuit controlling MOAP1 levels.","evidence":"In vitro ubiquitylation assay, siRNA knockdown of Cdh1, and immunoprecipitation","pmids":["22529100"],"confidence":"High","gaps":["Whether additional ligases contribute to MOAP1 turnover was not excluded","How apoptotic signals inhibit APC/C(Cdh1) toward MOAP1 not defined"]},{"year":2016,"claim":"Genetic loss-of-function in mice established MOAP1 as physiologically required for Fas-induced hepatocyte apoptosis and revealed it acts by enabling MTCH2-mediated tBid recruitment to mitochondria.","evidence":"MOAP1-deficient mouse model, Co-IP, Fas-induced apoptosis assay, tBid mitochondrial accumulation analysis","pmids":["27320914"],"confidence":"High","gaps":["The structural basis of the MOAP1–MTCH2 interaction was not determined","Whether this pathway operates outside hepatocytes was not tested"]},{"year":2016,"claim":"Identified UBR5 (with DYRK2) as a second destabilizing E3 ligase for MOAP1, linking MOAP1 stabilization to chemosensitization in cisplatin-resistant cancer cells.","evidence":"Co-IP, in vitro ubiquitylation assay, siRNA knockdown, and BAX activation assay","pmids":["27721409"],"confidence":"High","gaps":["Relative contributions of UBR5 versus APC/C(Cdh1) to MOAP1 turnover not quantified","DYRK2 phosphosites on MOAP1 not mapped"]},{"year":2018,"claim":"Showed RACK1 scaffolds TRAF2 to MOAP1 to drive K63-linked ubiquitination, adding a non-degradative ubiquitin signal to MOAP1 regulation.","evidence":"Co-IP, K63-linkage-specific ubiquitination assay, and interaction mapping","pmids":["29470995"],"confidence":"Medium","gaps":["The functional consequence of K63 ubiquitination on MOAP1 activity was not established","Single lab, no reciprocal in vivo validation"]},{"year":2021,"claim":"Expanded MOAP1 function beyond apoptosis by showing it binds LC3 via an N-terminal LIR motif to drive phagophore closure in starvation-induced autophagy.","evidence":"MOAP1 knockout cells, Halo-LC3 autophagosome completion assay, proteinase K protection, Co-IP, and LIR-mutant rescue","pmids":["33783314"],"confidence":"High","gaps":["How LC3 binding mechanically promotes membrane closure not resolved","Relationship between the autophagy and apoptotic functions of MOAP1 unclear"]},{"year":2021,"claim":"Crystal structures revealed a Gag capsid-like fold, reclassifying MOAP1 as a domesticated retroviral Gag protein and predicting capsid self-assembly capacity.","evidence":"X-ray crystallography with structural comparison to retroviral CA domains","pmids":["34357660"],"confidence":"High","gaps":["The structure did not address how the Gag fold relates to apoptotic or autophagy functions","Capsid assembly was inferred structurally, not demonstrated functionally"]},{"year":2025,"claim":"Demonstrated that MOAP1 self-assembles into RNA-containing capsid-like particles and is required for reproductive capacity, linking its Gag ancestry to an in vivo physiological role.","evidence":"Pnma4 knockout mouse model, electron microscopy/particle analysis, and reproductive phenotype characterization","pmids":["40263616"],"confidence":"Medium","gaps":["The cargo and function of the RNA-containing particles are undefined","Mechanistic link between capsid formation and fertility not established","Single lab"]},{"year":2025,"claim":"Placed MOAP1 in innate antiviral signaling, showing it interacts with MAVS and enhances TRIM25-mediated K63-ubiquitination of RIG-I to promote interferon responses.","evidence":"Proximity-based labeling (BioID), Co-IP, Pnma4 knockout mouse with viral susceptibility, K63-ubiquitination assay at RIG-I K657","pmids":["40929959"],"confidence":"Medium","gaps":["How MOAP1 facilitates the TRIM25–RIG-I reaction mechanistically is unresolved","Whether antiviral and apoptotic mitochondrial roles share machinery not tested","Single lab"]},{"year":null,"claim":"How a single Gag-derived protein integrates its distinct roles in BAX-dependent apoptosis, phagophore closure, RIG-I antiviral signaling, and capsid-mediated reproduction remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking the Gag capsid fold to apoptotic and autophagy activities","Functional relationship among the multiple ubiquitin signals on MOAP1 not integrated","Tissue-specific deployment of each function not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,7,10]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[8,9]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,4,10]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,5,2]}],"complexes":[],"partners":["RASSF1A","BAX","TRIM39","UBR5","MTCH2","RACK1","LC3","MAVS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96BY2","full_name":"Modulator of apoptosis 1","aliases":["Paraneoplastic antigen Ma4"],"length_aa":351,"mass_kda":39.5,"function":"Retrotransposon-derived protein that forms virion-like capsids (By similarity). Acts as an effector of BAX during apoptosis: enriched at outer mitochondria membrane and associates with BAX upon induction of apoptosis, facilitating BAX-dependent mitochondrial outer membrane permeabilization and apoptosis (PubMed:11060313, PubMed:16199525). Required for death receptor-dependent apoptosis (PubMed:11060313). When associated with RASSF1, promotes BAX conformational change and translocation to mitochondrial membranes in response to TNF and TNFSF10 stimulation (PubMed:15949439). Also promotes autophagy: promotes phagophore closure via association with ATG8 proteins (PubMed:33783314). Acts as an inhibitor of the NFE2L2/NRF2 pathway via interaction with SQSTM1: interaction promotes dissociation of SQSTM1 inclusion bodies that sequester KEAP1, relieving inactivation of the BCR(KEAP1) complex (PubMed:33393215)","subcellular_location":"Cytoplasm, cytosol; Mitochondrion outer membrane; Extracellular vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q96BY2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MOAP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MOAP1","total_profiled":1310},"omim":[{"mim_id":"612620","title":"RAS ASSOCIATION DOMAIN FAMILY, MEMBER 6; RASSF6","url":"https://www.omim.org/entry/612620"},{"mim_id":"609485","title":"MODULATOR OF APOPTOSIS 1; MOAP1","url":"https://www.omim.org/entry/609485"},{"mim_id":"605082","title":"RAS ASSOCIATION DOMAIN FAMILY PROTEIN 1; RASSF1","url":"https://www.omim.org/entry/605082"},{"mim_id":"604010","title":"PARANEOPLASTIC MA ANTIGEN 1; PNMA1","url":"https://www.omim.org/entry/604010"},{"mim_id":"300675","title":"PARANEOPLASTIC MA ANTIGEN 3; PNMA3","url":"https://www.omim.org/entry/300675"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":132.0}],"url":"https://www.proteinatlas.org/search/MOAP1"},"hgnc":{"alias_symbol":["MAP-1","PNMA4"],"prev_symbol":[]},"alphafold":{"accession":"Q96BY2","domains":[{"cath_id":"3.30.70.330","chopping":"2-94","consensus_level":"high","plddt":78.6946,"start":2,"end":94},{"cath_id":"-","chopping":"182-242","consensus_level":"high","plddt":87.7492,"start":182,"end":242},{"cath_id":"-","chopping":"248-349","consensus_level":"high","plddt":88.0424,"start":248,"end":349}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BY2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BY2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BY2-F1-predicted_aligned_error_v6.png","plddt_mean":78.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MOAP1","jax_strain_url":"https://www.jax.org/strain/search?query=MOAP1"},"sequence":{"accession":"Q96BY2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96BY2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96BY2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BY2"}},"corpus_meta":[{"pmid":"21383978","id":"PMC_21383978","title":"The bZIP transcription factor MoAP1 mediates the oxidative stress response and is critical for pathogenicity of the rice blast fungus Magnaporthe oryzae.","date":"2011","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/21383978","citation_count":247,"is_preprint":false},{"pmid":"16344548","id":"PMC_16344548","title":"The RASSF1A tumor suppressor activates Bax via MOAP-1.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16344548","citation_count":120,"is_preprint":false},{"pmid":"27721409","id":"PMC_27721409","title":"Downregulation of the proapoptotic protein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27721409","citation_count":58,"is_preprint":false},{"pmid":"22529100","id":"PMC_22529100","title":"The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22529100","citation_count":54,"is_preprint":false},{"pmid":"17535899","id":"PMC_17535899","title":"Inhibition of ubiquitin-mediated degradation of MOAP-1 by apoptotic stimuli promotes Bax function in mitochondria.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17535899","citation_count":54,"is_preprint":false},{"pmid":"19100260","id":"PMC_19100260","title":"TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process.","date":"2008","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19100260","citation_count":48,"is_preprint":false},{"pmid":"35999725","id":"PMC_35999725","title":"Polystyrene micro(nano)plastics damage the organelles of RBL-2H3 cells and promote MOAP-1 to induce apoptosis.","date":"2022","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/35999725","citation_count":41,"is_preprint":false},{"pmid":"31024598","id":"PMC_31024598","title":"Host-Induced Gene Silencing of MoAP1 Confers Broad-Spectrum Resistance to Magnaporthe oryzae.","date":"2019","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/31024598","citation_count":39,"is_preprint":false},{"pmid":"27560036","id":"PMC_27560036","title":"The thioredoxin MoTrx2 protein mediates reactive oxygen species (ROS) balance and controls pathogenicity as a target of the transcription factor MoAP1 in Magnaporthe oryzae.","date":"2016","source":"Molecular plant pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27560036","citation_count":39,"is_preprint":false},{"pmid":"22434376","id":"PMC_22434376","title":"miR-1228 prevents cellular apoptosis through targeting of MOAP1 protein.","date":"2012","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/22434376","citation_count":28,"is_preprint":false},{"pmid":"27320914","id":"PMC_27320914","title":"MOAP-1 Mediates Fas-Induced Apoptosis in Liver by Facilitating tBid Recruitment to Mitochondria.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27320914","citation_count":27,"is_preprint":false},{"pmid":"26269600","id":"PMC_26269600","title":"Modulator of apoptosis 1 (MOAP-1) is a tumor suppressor protein linked to the RASSF1A protein.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26269600","citation_count":26,"is_preprint":false},{"pmid":"35082905","id":"PMC_35082905","title":"Alpha-Mangostin Activates MOAP-1 Tumor Suppressor and Mitochondrial Signaling in MCF-7 Human Breast Cancer Cells.","date":"2022","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/35082905","citation_count":17,"is_preprint":false},{"pmid":"27294960","id":"PMC_27294960","title":"RASSF1A Site-Specific Methylation Hotspots in Cancer and Correlation with RASSF1C and MOAP-1.","date":"2016","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/27294960","citation_count":16,"is_preprint":false},{"pmid":"32377840","id":"PMC_32377840","title":"Tricistronic expression of MOAP-1, Bax and RASSF1A in cancer cells enhances chemo-sensitization that requires BH3L domain of MOAP-1.","date":"2020","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32377840","citation_count":14,"is_preprint":false},{"pmid":"29470995","id":"PMC_29470995","title":"RACK1/TRAF2 regulation of modulator of apoptosis-1 (MOAP-1).","date":"2018","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29470995","citation_count":11,"is_preprint":false},{"pmid":"35008453","id":"PMC_35008453","title":"Human Cytomegalovirus miR-UL70-3p Downregulates the H2O2-Induced Apoptosis by Targeting the Modulator of Apoptosis-1 (MOAP1).","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35008453","citation_count":11,"is_preprint":false},{"pmid":"33783314","id":"PMC_33783314","title":"The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/33783314","citation_count":10,"is_preprint":false},{"pmid":"35269511","id":"PMC_35269511","title":"Revealing the Roles of MOAP1 in Diseases: A Review.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35269511","citation_count":8,"is_preprint":false},{"pmid":"34357660","id":"PMC_34357660","title":"Structural evidence that MOAP1 and PEG10 are derived from retrovirus/retrotransposon Gag proteins.","date":"2021","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/34357660","citation_count":7,"is_preprint":false},{"pmid":"38810399","id":"PMC_38810399","title":"Adenovirus-mediated expression of MOAP-1, Bax and RASSF1A antagonizes chemo-drug resistance of human breast cancer cells expressing cancer stem cell markers.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/38810399","citation_count":7,"is_preprint":false},{"pmid":"40263616","id":"PMC_40263616","title":"The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.","date":"2025","source":"Nature aging","url":"https://pubmed.ncbi.nlm.nih.gov/40263616","citation_count":3,"is_preprint":false},{"pmid":"40929959","id":"PMC_40929959","title":"PNMA4 enhances anti-RNA virus immunity by promoting RIG-I signaling pathway.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40929959","citation_count":1,"is_preprint":false},{"pmid":"39041030","id":"PMC_39041030","title":"The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/39041030","citation_count":0,"is_preprint":false},{"pmid":"38798495","id":"PMC_38798495","title":"The retrotransposon - derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38798495","citation_count":0,"is_preprint":false},{"pmid":"39969102","id":"PMC_39969102","title":"Long non-coding RNA AK007111 mediates mast cells apoptosis via targeting of protein MOAP1.","date":"2025","source":"The Journal of asthma : official journal of the Association for the Care of Asthma","url":"https://pubmed.ncbi.nlm.nih.gov/39969102","citation_count":0,"is_preprint":false},{"pmid":"23236846","id":"PMC_23236846","title":"[PB1-F2 protein of influenza A virus interacts with human MOAP-1 protein].","date":"2012","source":"Wei sheng wu xue bao = Acta microbiologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/23236846","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15413,"output_tokens":3818,"usd":0.051755,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11488,"output_tokens":4072,"usd":0.07962,"stage2_stop_reason":"end_turn"},"total_usd":0.131375,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"RASSF1A directly interacts with MOAP-1, and this interaction is enhanced by activated K-Ras. RASSF1A activates Bax via MOAP-1, and activated K-Ras, RASSF1A, and MOAP-1 synergize to induce Bax activation and cell death. A tumor-derived point mutant of RASSF1A was defective for MOAP-1 interaction and Bax activation. Inhibition of RASSF1A by shRNA impaired K-Ras-mediated Bax activation.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, cell death assays, point mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, shRNA, point mutant, multiple orthogonal methods; independently replicated in subsequent studies\",\n      \"pmids\": [\"16344548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MOAP-1 is a short-lived protein (t½ ~25 min) constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP-1 by inhibiting its polyubiquitination. Elevated MOAP-1 sensitizes cells to apoptosis and promotes recombinant Bax-mediated cytochrome c release from isolated mitochondria. MOAP-1-depleted mitochondria become resistant to Bax-mediated cytochrome c release, and this resistance is restored by in vitro-translated MOAP-1.\",\n      \"method\": \"Cycloheximide chase, ubiquitination assay, isolated mitochondria cytochrome c release reconstitution with in vitro-translated protein\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with isolated mitochondria and in vitro-translated MOAP-1, multiple orthogonal methods, replicated across labs\",\n      \"pmids\": [\"17535899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIM39 is a MOAP-1-binding protein that extends MOAP-1 half-life by inhibiting its polyubiquitination process. TRIM39 elevates MOAP-1 levels in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. TRIM39 knockdown reduces sensitivity to etoposide-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, siRNA knockdown, isolated mitochondria cytochrome c release assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, functional mitochondrial reconstitution, siRNA; replicated and extended in 2012 paper\",\n      \"pmids\": [\"19100260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MOAP-1 is a substrate of the APC/C(Cdh1) ubiquitin ligase. TRIM39 (a RING domain E3 ligase) stabilizes MOAP-1 by directly inhibiting APC/C(Cdh1)-mediated ubiquitylation. Cdh1 knockdown stabilized MOAP-1, enhancing etoposide-induced Bax activation and apoptosis.\",\n      \"method\": \"In vitro ubiquitylation assay, siRNA knockdown of Cdh1, immunoprecipitation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitylation assay, siRNA epistasis, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"22529100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MOAP-1 deficiency in mice confers resistance to Fas-induced hepatocellular apoptosis and lethality. MOAP-1 interacts with MTCH2 at the outer mitochondrial membrane (OMM), and this interaction is required for MTCH2 to engage tBid. In the absence of MOAP-1, mitochondrial accumulation of tBid is markedly impaired, establishing that MOAP-1 facilitates Fas apoptotic signaling by promoting MTCH2-mediated tBid recruitment to mitochondria.\",\n      \"method\": \"MOAP-1-deficient mouse model, Co-immunoprecipitation, Fas-induced apoptosis assay, tBid mitochondrial accumulation analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout mouse model with defined phenotype, Co-IP identifying MTCH2 interaction, mechanistic tBid recruitment assay, multiple orthogonal methods\",\n      \"pmids\": [\"27320914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UBR5 (a HECT-family E3 ubiquitin ligase) physically interacts with MOAP-1 and ubiquitylates MOAP-1 in vitro, inhibiting MOAP-1 stability in cells. Dyrk2 kinase, a UBR5 interactor, cooperates with UBR5 in mediating MOAP-1 ubiquitylation. UBR5 knockdown increased MOAP-1 expression, enhanced Bax activation, and sensitized cisplatin-resistant ovarian cancer cells to apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitylation assay, siRNA knockdown, Bax activation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitylation assay plus Co-IP plus siRNA functional rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27721409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RACK1 associates with MOAP-1 via electrostatic interactions and recruits the E3 ligase TRAF2 to MOAP-1, resulting in K63-linked ubiquitination of MOAP-1. RACK1 was identified as a robust MOAP-1-interacting protein, linking scaffolding-mediated regulation to MOAP-1 ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63-linkage specificity), protein interaction mapping\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay identifying K63 linkage, single lab, two orthogonal methods\",\n      \"pmids\": [\"29470995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MOAP1 binds LC3 via an LC3-interacting region (LIR) motif at its N-terminal region, and this binding is required for efficient phagophore closure during starvation-induced autophagy. MOAP1-deficient cells are hypersensitive to starvation-induced cell death and exhibit predominantly unclosed phagophores. Re-expression of MOAP1, but not its LC3-binding defective mutant (MOAP1-LIR), restored EBSS-induced autophagy.\",\n      \"method\": \"MOAP1 knockout cells, Halo-tagged LC3 autophagosome completion assay, proteinase K protection assay, Co-immunoprecipitation, LIR mutant rescue\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout, LIR mutant rescue, autophagosome closure assay, proteinase K protection, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"33783314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"X-ray crystal structures of a stably folded domain of MOAP1 reveal high structural similarity to the C-terminal capsid (CA) domain of retroviral Gag proteins, classifying MOAP1 as a domesticated Gag protein derived from ancient retrovirus/retrotransposon integration.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with structural comparison; single lab but direct structural evidence\",\n      \"pmids\": [\"34357660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PNMA4 (MOAP1) self-assembles into capsid-like structures that exit human cells. Large PNMA4 particles were observed in mouse male gonadal tissue containing RNA, consistent with capsid formation. Pnma4 knockout mice become prematurely subfertile by six months with drops in sex hormone levels, gonadal atrophy, and abdominal obesity.\",\n      \"method\": \"Pnma4 knockout mouse model, electron microscopy/particle analysis, RNA-containing particle detection, reproductive phenotype characterization\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined reproductive phenotype, capsid-like particle observation, single lab\",\n      \"pmids\": [\"40263616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PNMA4/MOAP1 is a mitochondrial protein that interacts with MAVS (identified by proximity-based labeling). PNMA4 enhances the interaction between RIG-I and MAVS after RNA virus infection and facilitates K63-linked polyubiquitination of RIG-I at lysine 657 by TRIM25. Pnma4 knockout mice are more susceptible to RNA virus infection, and PNMA4 deficiency reduces RNA virus-induced activation of antiviral (IFN-β) pathways.\",\n      \"method\": \"Proximity-based labeling (BioID), Co-immunoprecipitation, Pnma4 knockout mouse model, ubiquitination assay (K63-linkage at K657)\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling, Co-IP, KO mouse with viral susceptibility phenotype, ubiquitination assay; single lab\",\n      \"pmids\": [\"40929959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Influenza A virus PB1-F2 protein specifically interacts with human MOAP-1, as demonstrated by yeast two-hybrid, GST pull-down, and Co-IP assays. PB1-F2 upregulates exogenous MOAP-1 protein levels.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, Co-immunoprecipitation, Western blot\",\n      \"journal\": \"Wei sheng wu xue bao = Acta microbiologica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — multiple binding assays but no functional mechanistic follow-up, single lab\",\n      \"pmids\": [\"23236846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MOAP-1 overexpression in cancer cell lines reduces tumorigenesis and upregulates genes in apoptosis (p53, Fas, MST1), DNA damage control (PARP, ATM), and cell metabolism (IR-α, IR-β, AMPK), and stabilizes microtubules. Rapid proteasomal degradation of MOAP-1 can be reversed by the proteasome inhibitor MG132.\",\n      \"method\": \"Overexpression, xenograft assay, proliferation assay, DNA microarray, proteasome inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with xenograft and microarray, multiple methods; single lab\",\n      \"pmids\": [\"26269600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The BH3L domain of MOAP-1 is required for its pro-apoptotic activity. A BH3L-deletion mutant (MOAP-1ΔBHB3L) inhibited the apoptotic activity of the MOAP-1/Bax/RASSF1A tricistronic construct and conferred chemo-drug resistance in stable clones, whereas wild-type MOAP-1 in the tricistronic construct promoted dose-dependent apoptosis and chemo-sensitization.\",\n      \"method\": \"Domain deletion mutagenesis, tricistronic expression construct, cell viability assay, Annexin-V staining, mouse xenograft\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with functional readout in multiple cell models including xenograft; single lab\",\n      \"pmids\": [\"32377840\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MOAP1 (PNMA4) is a short-lived outer mitochondrial membrane protein, constitutively degraded by the ubiquitin-proteasome system via APC/C(Cdh1) and UBR5, that upon apoptotic stabilization binds and activates BAX to promote cytochrome c release; it functions downstream of the RASSF1A–K-Ras axis, facilitates Fas-induced apoptosis by promoting MTCH2-mediated tBid recruitment to mitochondria, participates in starvation-induced autophagy by binding LC3 via an N-terminal LIR motif to promote phagophore closure, enhances antiviral RIG-I/MAVS signaling by facilitating TRIM25-mediated K63-ubiquitination of RIG-I, and self-assembles into capsid-like structures (reflecting its domesticated retroviral Gag origin) required for reproductive capacity in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MOAP1 (PNMA4) is a short-lived outer mitochondrial membrane protein that functions as a rheostat for apoptotic commitment, acting at the convergence of multiple death signals to drive BAX-dependent mitochondrial outer membrane permeabilization [#1, #0]. Under basal conditions it is held at low abundance by constitutive ubiquitin-proteasome turnover (t\\u00bd ~25 min), and apoptotic stimuli stabilize the protein by inhibiting its polyubiquitination, allowing it to promote BAX-mediated cytochrome c release from mitochondria [#1]. Its degradation is controlled by a layered set of ubiquitin ligases: the APC/C(Cdh1) complex and the HECT ligase UBR5 (cooperating with DYRK2) target MOAP1 for destruction, while the RING ligase TRIM39 stabilizes it by antagonizing APC/C(Cdh1)-mediated ubiquitylation, and depleting the destabilizing ligases enhances BAX activation and chemosensitizes cancer cells [#3, #5, #2]. MOAP1 acts downstream of a RASSF1A\\u2013K-Ras axis, where activated K-Ras enhances RASSF1A binding to MOAP1 to synergistically activate BAX and induce death [#0], and its pro-apoptotic output depends on a BH3-like (BH3L) domain [#13]. In Fas-induced hepatocyte apoptosis it operates by binding MTCH2 at the outer mitochondrial membrane to enable MTCH2-dependent recruitment of tBid to mitochondria [#4]. Beyond apoptosis, MOAP1 binds LC3 through an N-terminal LIR motif to promote phagophore closure during starvation-induced autophagy [#7], and at the mitochondrion it interacts with MAVS to enhance RIG-I/MAVS antiviral signaling by facilitating TRIM25-mediated K63-ubiquitination of RIG-I [#10]. Structurally, MOAP1 contains a folded domain resembling the retroviral Gag capsid domain and self-assembles into RNA-containing capsid-like particles, with loss of the gene causing premature subfertility and gonadal atrophy in mice, identifying it as a domesticated Gag protein with a role in reproductive capacity [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established MOAP1 as the effector linking the RASSF1A\\u2013K-Ras tumor-suppressor axis to BAX activation, answering how this signaling module triggers apoptosis.\",\n      \"evidence\": \"Co-IP, shRNA knockdown, point-mutant analysis, and cell death assays in human cells\",\n      \"pmids\": [\"16344548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical mechanism by which MOAP1 activates BAX\", \"Did not address how MOAP1 abundance is controlled\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed MOAP1 is a constitutively degraded, short-lived protein stabilized by apoptotic stimuli, defining abundance control as the switch governing its pro-apoptotic activity at mitochondria.\",\n      \"evidence\": \"Cycloheximide chase, ubiquitination assay, and isolated-mitochondria cytochrome c release reconstitution with in vitro-translated protein\",\n      \"pmids\": [\"17535899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ubiquitin ligase responsible for basal turnover was not identified\", \"The molecular interface with BAX was not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified TRIM39 as a stabilizing partner that extends MOAP1 half-life, providing the first positive regulator of MOAP1 abundance.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, cycloheximide chase, siRNA, and isolated-mitochondria cytochrome c release assay\",\n      \"pmids\": [\"19100260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The destabilizing ligase that TRIM39 antagonizes was not yet known\", \"Mechanism of TRIM39 inhibition of ubiquitylation undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined APC/C(Cdh1) as the E3 ligase that degrades MOAP1 and showed TRIM39 stabilizes MOAP1 by directly inhibiting this ligase, resolving the regulatory circuit controlling MOAP1 levels.\",\n      \"evidence\": \"In vitro ubiquitylation assay, siRNA knockdown of Cdh1, and immunoprecipitation\",\n      \"pmids\": [\"22529100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional ligases contribute to MOAP1 turnover was not excluded\", \"How apoptotic signals inhibit APC/C(Cdh1) toward MOAP1 not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic loss-of-function in mice established MOAP1 as physiologically required for Fas-induced hepatocyte apoptosis and revealed it acts by enabling MTCH2-mediated tBid recruitment to mitochondria.\",\n      \"evidence\": \"MOAP1-deficient mouse model, Co-IP, Fas-induced apoptosis assay, tBid mitochondrial accumulation analysis\",\n      \"pmids\": [\"27320914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The structural basis of the MOAP1\\u2013MTCH2 interaction was not determined\", \"Whether this pathway operates outside hepatocytes was not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified UBR5 (with DYRK2) as a second destabilizing E3 ligase for MOAP1, linking MOAP1 stabilization to chemosensitization in cisplatin-resistant cancer cells.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitylation assay, siRNA knockdown, and BAX activation assay\",\n      \"pmids\": [\"27721409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of UBR5 versus APC/C(Cdh1) to MOAP1 turnover not quantified\", \"DYRK2 phosphosites on MOAP1 not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed RACK1 scaffolds TRAF2 to MOAP1 to drive K63-linked ubiquitination, adding a non-degradative ubiquitin signal to MOAP1 regulation.\",\n      \"evidence\": \"Co-IP, K63-linkage-specific ubiquitination assay, and interaction mapping\",\n      \"pmids\": [\"29470995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The functional consequence of K63 ubiquitination on MOAP1 activity was not established\", \"Single lab, no reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded MOAP1 function beyond apoptosis by showing it binds LC3 via an N-terminal LIR motif to drive phagophore closure in starvation-induced autophagy.\",\n      \"evidence\": \"MOAP1 knockout cells, Halo-LC3 autophagosome completion assay, proteinase K protection, Co-IP, and LIR-mutant rescue\",\n      \"pmids\": [\"33783314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LC3 binding mechanically promotes membrane closure not resolved\", \"Relationship between the autophagy and apoptotic functions of MOAP1 unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Crystal structures revealed a Gag capsid-like fold, reclassifying MOAP1 as a domesticated retroviral Gag protein and predicting capsid self-assembly capacity.\",\n      \"evidence\": \"X-ray crystallography with structural comparison to retroviral CA domains\",\n      \"pmids\": [\"34357660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The structure did not address how the Gag fold relates to apoptotic or autophagy functions\", \"Capsid assembly was inferred structurally, not demonstrated functionally\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that MOAP1 self-assembles into RNA-containing capsid-like particles and is required for reproductive capacity, linking its Gag ancestry to an in vivo physiological role.\",\n      \"evidence\": \"Pnma4 knockout mouse model, electron microscopy/particle analysis, and reproductive phenotype characterization\",\n      \"pmids\": [\"40263616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The cargo and function of the RNA-containing particles are undefined\", \"Mechanistic link between capsid formation and fertility not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed MOAP1 in innate antiviral signaling, showing it interacts with MAVS and enhances TRIM25-mediated K63-ubiquitination of RIG-I to promote interferon responses.\",\n      \"evidence\": \"Proximity-based labeling (BioID), Co-IP, Pnma4 knockout mouse with viral susceptibility, K63-ubiquitination assay at RIG-I K657\",\n      \"pmids\": [\"40929959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How MOAP1 facilitates the TRIM25\\u2013RIG-I reaction mechanistically is unresolved\", \"Whether antiviral and apoptotic mitochondrial roles share machinery not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single Gag-derived protein integrates its distinct roles in BAX-dependent apoptosis, phagophore closure, RIG-I antiviral signaling, and capsid-mediated reproduction remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking the Gag capsid fold to apoptotic and autophagy activities\", \"Functional relationship among the multiple ubiquitin signals on MOAP1 not integrated\", \"Tissue-specific deployment of each function not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 7, 10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [4, 1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 4, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 5, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RASSF1A\", \"BAX\", \"TRIM39\", \"UBR5\", \"MTCH2\", \"RACK1\", \"LC3\", \"MAVS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}