{"gene":"TRIAP1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2013,"finding":"TRIAP1 (p53CSV) forms a complex with PRELI in the mitochondrial intermembrane space (IMS) that exerts lipid transfer activity in vitro, supplying phosphatidic acid (PA) for cardiolipin (CL) synthesis in the inner membrane. Loss of TRIAP1 or PRELI impairs CL accumulation, facilitates cytochrome c release, and renders cells vulnerable to apoptosis; survival is rescued by exogenous phosphatidylglycerol.","method":"Co-immunoprecipitation, in vitro lipid transfer assay, loss-of-function (siRNA/KO) with cytochrome c release and apoptosis readouts, lipid rescue experiment","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro lipid transfer reconstitution, complex identification, genetic loss-of-function with defined biochemical rescue, multiple orthogonal methods in single rigorous study","pmids":["23931759"],"is_preprint":false},{"year":2010,"finding":"Mdm35 (the yeast ortholog of TRIAP1) binds Ups1 and Ups2 (PRELI-family proteins) in the mitochondrial IMS, protecting them from proteolytic degradation by Yme1 and Atp23 and ensuring their import, thereby regulating cardiolipin and phosphatidylethanolamine levels in mitochondrial membranes.","method":"Yeast genetics, co-immunoprecipitation, protease-sensitivity assays, deletion mutants with lipid quantification","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic deletion with defined lipid phenotypes, protease assays, independently replicated in follow-up studies","pmids":["20657548"],"is_preprint":false},{"year":2016,"finding":"Ups2-Mdm35 complexes (SLMO2-TRIAP1 in humans) function as phosphatidylserine (PS)-specific lipid transfer proteins in the mitochondrial IMS, enabling PS decarboxylation to phosphatidylethanolamine (PE) by Psd1 at the inner membrane; a recombinant Ups2-Mdm35 fusion protein exhibits PS transfer activity between liposomes in vitro.","method":"In vitro liposome lipid transfer assay with recombinant fusion protein, yeast null mutants with radiolabeled PS-to-PE conversion, genetic analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of lipid transfer, confirmed in two independent papers (PMID 27241913, 27354379) with orthogonal methods","pmids":["27241913","27354379"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of the Ups1-Mdm35-PA complex (yeast ortholog of TRIAP1-PRELI) reveals that Ups1 forms a barrel-like structure with a tunnel-like PA-binding pocket covered by helix α2, while Mdm35 adopts a three-helical clamp-like structure wrapping around Ups1. Hydrophobic residues lining the pocket and helix α2, plus a hydrophilic surface patch near the PA phosphate-binding site, are critical for PA binding and transfer as shown by mutagenesis.","method":"X-ray crystallography, site-directed mutagenesis, in vitro PA-binding and transfer assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis and in vitro transfer assays in a single rigorous study","pmids":["26071601"],"is_preprint":false},{"year":2005,"finding":"TRIAP1 (p53CSV) is a p53 target gene containing a p53-binding site in its second exon. Overexpression protects cells from DNA-damage-induced apoptosis, while siRNA knockdown enhances apoptosis. TRIAP1 interacts with Hsp70 in the cytoplasm, likely inhibiting apoptosome formation via Apaf-1.","method":"siRNA knockdown, overexpression, apoptosis assays, co-immunoprecipitation with Hsp70, reporter/binding-site analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — single lab, Co-IP with Hsp70, loss- and gain-of-function with apoptosis readout, p53-binding site identification; mechanism downstream of Hsp70 partially inferred","pmids":["15735003"],"is_preprint":false},{"year":2013,"finding":"A genome-wide genetic screen identified TRIAP1 as a specific repressor of p21 (CDKN1A) expression upon p53 activation; TRIAP1 depletion slows cell-cycle progression without broadly affecting PUMA-mediated apoptosis, placing TRIAP1 as a pathway-specific coregulator of the p53 transcriptional program.","method":"Genome-wide RNAi screen, targeted siRNA depletion, p21/PUMA expression readouts, cell-cycle analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen followed by targeted validation, single lab, two orthogonal readouts (p21 expression, cell-cycle)","pmids":["23684607"],"is_preprint":false},{"year":2016,"finding":"TRIAP1 knockdown in NPC cells induces mitochondrial fragmentation, membrane potential alteration, and cytochrome c release from mitochondria into the cytosol, enhancing apoptosis; these effects are phenocopied by miR-320b overexpression and reversed by TRIAP1 restoration.","method":"siRNA knockdown, overexpression rescue, mitochondrial morphology imaging, membrane potential assay, cytochrome c fractionation, in vivo xenograft","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple cellular assays in single lab, in vivo confirmation, rescue experiment; mechanism limited to cytochrome c release without further biochemical dissection","pmids":["27428374"],"is_preprint":false},{"year":2015,"finding":"TRIAP1 inhibits caspase-9 activation in the cytoplasm (apoptosome-blocking activity); stable overexpression of TRIAP1 in breast cancer cells increases doxorubicin-resistant clone formation, while siRNA knockdown of TRIAP1 in drug-resistant cells impairs growth in the presence of doxorubicin.","method":"Stable transfection/overexpression, siRNA, caspase-9 activity assay, colony formation under drug selection","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — caspase assay plus functional drug-resistance readout, replicated concept from Park 2005; mechanistic detail limited in abstract","pmids":["25998939"],"is_preprint":false},{"year":2016,"finding":"Stable shRNA-mediated silencing of TRIAP1 in RPMI8226 multiple myeloma cells increases late apoptosis accompanied by upregulation of APAF1 and caspase-9 expression, and activation of caspase-9 and caspase-3/7, establishing that TRIAP1 suppresses the APAF1/caspase-9 apoptosome pathway.","method":"Lentiviral shRNA stable knockdown, flow cytometry (annexin V/PI), qRT-PCR for APAF1 and caspase-9, caspase activity assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable genetic knockdown with multiple orthogonal apoptosis readouts; single lab, single cell line","pmids":["27032384"],"is_preprint":false},{"year":2025,"finding":"TRIAP1 is imported into the mitochondrial IMS via the MIA40 oxidative folding relay. In its reduced cytosolic state, TRIAP1 rapidly forms a hydrophobic, alpha-helical, marginally stable molten globule intermediate that biases oxidative folding toward a non-native Cys37-Cys47 kinetic trap. MIA40 accelerates TRIAP1 folding by 30-fold by driving oxidation of the inner disulfide bond (Cys18-Cys37) and then the outer disulfide bond (Cys8-Cys47), yielding the native two-disulfide-bridged structure and bypassing the kinetic trap.","method":"NMR, biochemical oxidative folding assays, disulfide-bond mapping, mutagenesis, in vitro MIA40 interaction assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural (NMR) plus in vitro biochemical reconstitution of MIA40-assisted folding with disulfide identification; single lab but multiple orthogonal methods","pmids":["39909379"],"is_preprint":false},{"year":2023,"finding":"TRIAP1 upregulation in human cells after nocodazole treatment retains cytochrome c in mitochondria, opposing partial caspase activation caused by prolonged mitotic arrest, thereby enabling escape from the G1 arrest that follows mitotic slippage. Decreasing TRIAP1 re-sensitizes cells to nocodazole.","method":"Long-term cell-fate tracking, cytochrome c localization (mitochondrial fractionation/imaging), caspase activation assays, siRNA knockdown and overexpression, proliferation assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cytochrome c retention assay, bidirectional manipulation (OE and KD), single lab","pmids":["36917609"],"is_preprint":false},{"year":2023,"finding":"Exercise training downregulates CHCHD4, a mitochondrial disulfide relay carrier, which decreases import of TRIAP1 into mitochondria. Reduced mitochondrial TRIAP1 lowers cardiolipin levels and promotes VDAC oligomerization in skeletal muscle, facilitating mtDNA release and activating cGAS-STING/NFKB innate immune signaling, ultimately downregulating MyoD and promoting oxidative slow-twitch fiber formation.","method":"Mouse genetic model (CHCHD4 haploinsufficiency), cardiolipin quantification, VDAC oligomerization assay, mtDNA release assay, cGAS-STING/NFKB pathway analysis, skeletal muscle fiber-type characterization","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with multiple orthogonal mechanistic readouts; TRIAP1 import dependency on CHCHD4 is central finding but full reconstitution not performed","pmids":["38157298"],"is_preprint":false},{"year":2025,"finding":"SLMO2 (PRELI) interacts with TRIAP1 in ovarian cancer cells, enhancing mitochondrial membrane potential, reducing ROS, and inhibiting autophagy-dependent apoptosis. Co-expression of SLMO2 and TRIAP1 promotes tumor cell growth in vivo.","method":"Co-immunoprecipitation/interaction assay, flow cytometry, western blotting for autophagy markers, mitochondrial membrane potential assay, ROS measurement, xenograft mouse model","journal":"Histology and histopathology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — interaction demonstrated, multiple functional readouts, in vivo confirmation; mechanistic detail on autophagy pathway is limited in the abstract","pmids":["40654025"],"is_preprint":false},{"year":2022,"finding":"In colorectal cancer cells, TRIAP1 depletion perturbs mitochondrial ultrastructure and alters endoplasmic reticulum-dependent lipid homeostasis without a major impact on cardiolipin levels or mitochondrial respiratory activity. TRIAP1 depletion also induces a p53-mediated stress response and confers resistance to glutamine deprivation, indicating extramitochondrial roles for TRIAP1 in lipid homeostasis and metabolic stress adaptation.","method":"shRNA stable knockdown, electron microscopy (mitochondrial ultrastructure), cardiolipin quantification, metabolomics, p53 pathway reporter assays, glutamine deprivation survival assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab; cardiolipin unchanged finding is a notable negative informing mechanism","pmids":["36387192"],"is_preprint":false},{"year":2020,"finding":"TRIAP1 knockdown in NSCLC cells (A549, H460) decreases expression of multiple antioxidant proteins (TMX1, TMX2, TXN, GLRX2, GLRX3, PRDX3, PRDX4, PRDX6), impairs radiation-induced upregulation of these proteins, and increases intracellular reactive oxygen species, thereby reducing radioresistance.","method":"siRNA knockdown, western blotting for antioxidant proteins, ROS measurement, cell viability and apoptosis assays after irradiation","journal":"Thoracic cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with protein panel; no direct mechanistic link between TRIAP1 and redox enzyme regulation established","pmids":["32096592"],"is_preprint":false}],"current_model":"TRIAP1 is a small, cysteine-rich mitochondrial IMS protein imported via the MIA40 oxidative folding relay that forms a stable complex with PRELI/SLMO2 and functions as a phosphatidic acid (PA) and phosphatidylserine (PS) lipid transfer protein, supplying substrates for cardiolipin and phosphatidylethanolamine synthesis at the inner membrane; loss of TRIAP1 reduces cardiolipin levels, triggers cytochrome c release, and activates the APAF1/caspase-9 apoptosome, while in the cytoplasm TRIAP1 additionally binds HSP70 to block apoptosome assembly, and its transcription is induced by p53 to promote cell survival under sub-lethal genotoxic stress."},"narrative":{"mechanistic_narrative":"TRIAP1 is a small cysteine-rich mitochondrial intermembrane-space (IMS) protein that, together with PRELI-family partners, functions as an intramitochondrial lipid transfer module governing phospholipid biosynthesis and apoptotic priming [PMID:23931759, PMID:27241913, PMID:27354379]. It is imported into the IMS through the MIA40/CHCHD4 oxidative disulfide-relay, which accelerates folding of the reduced cytosolic protein toward its native two-disulfide structure and away from a non-native kinetic trap [PMID:39909379, PMID:38157298]. In the IMS TRIAP1 forms a stable complex with PRELI/Ups1 that transfers phosphatidic acid to the inner membrane to support cardiolipin synthesis [PMID:23931759], while the SLMO2/Ups2-TRIAP1 complex transfers phosphatidylserine to enable its decarboxylation to phosphatidylethanolamine [PMID:27241913, PMID:27354379]; the yeast ortholog Mdm35 additionally stabilizes its PRELI-family partners against proteolysis, and crystallography of the Ups1-Mdm35-PA complex defines a barrel-like PA-binding pocket clamped by the Mdm35 three-helix fold [PMID:20657548, PMID:26071601]. By maintaining cardiolipin, TRIAP1 restrains cytochrome c release and suppresses the APAF1/caspase-9 apoptosome, so its loss fragments mitochondria, releases cytochrome c, and activates caspase-9/-3 [PMID:23931759, PMID:27428374, PMID:27032384]. TRIAP1 is a p53 target gene that promotes survival under sub-lethal genotoxic stress, binds cytoplasmic HSP70 to block apoptosome assembly, and acts as a pathway-specific repressor of p21 within the p53 program [PMID:15735003, PMID:23684607]. Through these activities TRIAP1 confers chemo- and radio-resistance and enables survival following mitotic slippage by retaining cytochrome c in mitochondria [PMID:25998939, PMID:36917609].","teleology":[{"year":2005,"claim":"Establishing TRIAP1 as a p53-inducible survival factor answered how the gene is regulated and connected it to apoptosis suppression via the apoptosome.","evidence":"p53-binding-site identification, gain/loss-of-function apoptosis assays, and Hsp70 Co-IP in human cells","pmids":["15735003"],"confidence":"Medium","gaps":["Mechanism downstream of HSP70 binding only inferred","No structural basis for HSP70 interaction"]},{"year":2010,"claim":"Yeast genetics defined Mdm35 (TRIAP1 ortholog) as a chaperone/stabilizer of PRELI-family proteins, linking the protein to mitochondrial phospholipid regulation for the first time.","evidence":"Reciprocal Co-IP, protease-sensitivity assays, and deletion mutants with cardiolipin/PE quantification in yeast","pmids":["20657548"],"confidence":"High","gaps":["Direct lipid transfer activity not yet demonstrated","Human ortholog function not addressed"]},{"year":2013,"claim":"Demonstrating TRIAP1-PRELI lipid transfer activity and its requirement for cardiolipin accumulation explained mechanistically how TRIAP1 controls cytochrome c release and apoptotic vulnerability.","evidence":"Co-IP, in vitro PA lipid transfer assay, loss-of-function with cytochrome c release readouts, and phosphatidylglycerol rescue in human cells","pmids":["23931759"],"confidence":"High","gaps":["Stoichiometry and dynamics of transfer in vivo unresolved","Structural basis not defined in this study"]},{"year":2013,"claim":"A genome-wide screen revealed TRIAP1 as a pathway-specific repressor of p21, refining its role within the p53 transcriptional program beyond apoptosis suppression.","evidence":"Genome-wide RNAi screen with targeted validation, p21/PUMA expression and cell-cycle readouts","pmids":["23684607"],"confidence":"Medium","gaps":["Molecular mechanism of p21 repression unknown","Whether mitochondrial or cytoplasmic TRIAP1 mediates this is unclear"]},{"year":2015,"claim":"The Ups1-Mdm35-PA crystal structure provided the atomic architecture of the lipid-binding pocket, converting the functional model into a structural mechanism.","evidence":"X-ray crystallography with site-directed mutagenesis and in vitro PA-binding/transfer assays","pmids":["26071601"],"confidence":"High","gaps":["Conformational changes during lipid loading/unloading not captured","Structure of human TRIAP1 complex not solved"]},{"year":2015,"claim":"Linking TRIAP1 to caspase-9 inhibition and doxorubicin resistance extended its survival function into a chemoresistance context.","evidence":"Stable overexpression/siRNA, caspase-9 activity assay, and colony formation under drug selection in breast cancer cells","pmids":["25998939"],"confidence":"Medium","gaps":["Mechanistic detail limited","Direct caspase-9/apoptosome binding not shown"]},{"year":2016,"claim":"Identifying Ups2-Mdm35/SLMO2-TRIAP1 as a PS-specific transfer protein enabling PS-to-PE conversion broadened TRIAP1's substrate range and explained its role in PE biosynthesis.","evidence":"In vitro liposome transfer with recombinant fusion protein and radiolabeled PS-to-PE conversion in yeast null mutants","pmids":["27241913","27354379"],"confidence":"High","gaps":["Substrate selectivity determinants between PA and PS partners not fully resolved","In vivo flux control quantification incomplete"]},{"year":2016,"claim":"Cellular and in vivo loss-of-function studies confirmed that TRIAP1 maintains mitochondrial integrity and represses the APAF1/caspase-9 apoptosome.","evidence":"siRNA/shRNA knockdown with rescue, mitochondrial morphology/membrane-potential imaging, cytochrome c fractionation, and qRT-PCR/caspase assays in NPC and myeloma cells plus xenografts","pmids":["27428374","27032384"],"confidence":"Medium","gaps":["Whether effects are solely cardiolipin-dependent not dissected","Direct apoptosome-component binding not demonstrated"]},{"year":2022,"claim":"Showing that TRIAP1 depletion alters ER-dependent lipid homeostasis without changing cardiolipin in colorectal cells revealed context-dependent, possibly extramitochondrial, metabolic roles.","evidence":"Stable shRNA knockdown with electron microscopy, cardiolipin quantification, metabolomics, p53 reporters, and glutamine-deprivation survival assays","pmids":["36387192"],"confidence":"Medium","gaps":["Mechanism of ER lipid homeostasis effect unknown","Reconciliation with cardiolipin-dependent models in other cell types unresolved"]},{"year":2023,"claim":"Two studies connected TRIAP1 mitochondrial import and abundance to physiological outcomes: cytochrome c retention during mitotic slippage and CHCHD4-dependent control of cardiolipin, VDAC oligomerization, and innate-immune signaling in muscle.","evidence":"Cell-fate tracking with cytochrome c localization in human cells, and CHCHD4-haploinsufficient mouse model with cardiolipin/VDAC/mtDNA-release and cGAS-STING readouts","pmids":["36917609","38157298"],"confidence":"Medium","gaps":["TRIAP1 import dependency on CHCHD4 not reconstituted in vitro","Direct contribution of TRIAP1 versus pathway-wide CHCHD4 effects hard to separate"]},{"year":2025,"claim":"Mapping the MIA40-assisted oxidative folding pathway of TRIAP1 explained how the reduced cytosolic protein attains its native disulfide-bonded IMS structure, and a tumor study reaffirmed the SLMO2-TRIAP1 interaction in promoting survival.","evidence":"NMR, disulfide-bond mapping, in vitro MIA40 folding assays; plus Co-IP and functional/xenograft assays in ovarian cancer cells","pmids":["39909379","40654025"],"confidence":"High","gaps":["In vivo kinetics of TRIAP1 import not measured","How folding state couples to lipid-transfer competence unknown"]},{"year":null,"claim":"How TRIAP1 partitions between its mitochondrial lipid-transfer role and its cytoplasmic apoptosome/HSP70-dependent and p53-coregulatory functions, and whether these are mechanistically coupled, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the human TRIAP1-PRELI or TRIAP1-HSP70 complex","Quantitative determinants of substrate (PA vs PS) selectivity unknown","Cell-type-dependent cardiolipin requirement not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7,8]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,6,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,9]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,6,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,11]}],"complexes":["TRIAP1-PRELI/SLMO2 lipid transfer complex"],"partners":["PRELID1","SLMO2","HSP70","MIA40/CHCHD4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43715","full_name":"TP53-regulated inhibitor of apoptosis 1","aliases":["Protein 15E1.1","WF-1","p53-inducible cell-survival factor","p53CSV"],"length_aa":76,"mass_kda":8.8,"function":"Involved in the modulation of the mitochondrial apoptotic pathway by ensuring the accumulation of cardiolipin (CL) in mitochondrial membranes. In vitro, the TRIAP1:PRELID1 complex mediates the transfer of phosphatidic acid (PA) between liposomes and probably functions as a PA transporter across the mitochondrion intermembrane space to provide PA for CL synthesis in the inner membrane (PubMed:23931759). Likewise, the TRIAP1:PRELID3A complex mediates the transfer of phosphatidic acid (PA) between liposomes (in vitro) and probably functions as a PA transporter across the mitochondrion intermembrane space (in vivo) (PubMed:26071602). Mediates cell survival by inhibiting activation of caspase-9 which prevents induction of apoptosis (PubMed:15735003)","subcellular_location":"Mitochondrion; Mitochondrion intermembrane space","url":"https://www.uniprot.org/uniprotkb/O43715/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIAP1","classification":"Common Essential","n_dependent_lines":1171,"n_total_lines":1208,"dependency_fraction":0.9693708609271523},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ALDH16A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRIAP1","total_profiled":1310},"omim":[{"mim_id":"620754","title":"PRELI DOMAIN-CONTAINING PROTEIN 3B; PRELID3B","url":"https://www.omim.org/entry/620754"},{"mim_id":"616545","title":"PRELI DOMAIN-CONTAINING PROTEIN 3A; PRELID3A","url":"https://www.omim.org/entry/616545"},{"mim_id":"614943","title":"TP53-REGULATED INHIBITOR OF APOPTOSIS 1; TRIAP1","url":"https://www.omim.org/entry/614943"},{"mim_id":"605733","title":"PRELI DOMAIN-CONTAINING PROTEIN 1; PRELID1","url":"https://www.omim.org/entry/605733"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIAP1"},"hgnc":{"alias_symbol":["P53CSV","WF-1","HSPC132","p53CSV","MDM35"],"prev_symbol":[]},"alphafold":{"accession":"O43715","domains":[{"cath_id":"-","chopping":"5-54","consensus_level":"high","plddt":94.0234,"start":5,"end":54}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43715","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43715-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43715-F1-predicted_aligned_error_v6.png","plddt_mean":87.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIAP1","jax_strain_url":"https://www.jax.org/strain/search?query=TRIAP1"},"sequence":{"accession":"O43715","fasta_url":"https://rest.uniprot.org/uniprotkb/O43715.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43715/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43715"}},"corpus_meta":[{"pmid":"23931759","id":"PMC_23931759","title":"TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid.","date":"2013","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23931759","citation_count":167,"is_preprint":false},{"pmid":"20657548","id":"PMC_20657548","title":"Regulation of mitochondrial phospholipids by Ups1/PRELI-like proteins depends on proteolysis and Mdm35.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20657548","citation_count":143,"is_preprint":false},{"pmid":"27241913","id":"PMC_27241913","title":"MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria.","date":"2016","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27241913","citation_count":130,"is_preprint":false},{"pmid":"27354379","id":"PMC_27354379","title":"Phosphatidylserine transport by Ups2-Mdm35 in respiration-active mitochondria.","date":"2016","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27354379","citation_count":64,"is_preprint":false},{"pmid":"15735003","id":"PMC_15735003","title":"p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15735003","citation_count":60,"is_preprint":false},{"pmid":"23684607","id":"PMC_23684607","title":"A genetic screen identifies TCF3/E2A and TRIAP1 as pathway-specific regulators of the cellular response to p53 activation.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23684607","citation_count":60,"is_preprint":false},{"pmid":"27428374","id":"PMC_27428374","title":"Overexpression of Mitochondria Mediator Gene TRIAP1 by miR-320b Loss Is Associated with Progression in Nasopharyngeal Carcinoma.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27428374","citation_count":50,"is_preprint":false},{"pmid":"26071601","id":"PMC_26071601","title":"Structural basis of intramitochondrial phosphatidic acid transport mediated by Ups1-Mdm35 complex.","date":"2015","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/26071601","citation_count":48,"is_preprint":false},{"pmid":"19171422","id":"PMC_19171422","title":"SAGE analysis highlights the importance of p53csv, ddx5, mapkapk2 and ranbp2 to multiple myeloma tumorigenesis.","date":"2009","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/19171422","citation_count":44,"is_preprint":false},{"pmid":"25998939","id":"PMC_25998939","title":"Apoptosis inhibitor TRIAP1 is a novel effector of drug resistance.","date":"2015","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25998939","citation_count":37,"is_preprint":false},{"pmid":"28588697","id":"PMC_28588697","title":"MicroRNA-18a inhibits ovarian cancer growth via directly targeting TRIAP1 and IPMK.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28588697","citation_count":34,"is_preprint":false},{"pmid":"33981772","id":"PMC_33981772","title":"Circular RNA circPVT1 Contributes to Doxorubicin (DXR) Resistance of Osteosarcoma Cells by Regulating TRIAP1 via miR-137.","date":"2021","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/33981772","citation_count":28,"is_preprint":false},{"pmid":"30871022","id":"PMC_30871022","title":"Progression-Related Loss of Stromal Caveolin 1 Levels Mediates Radiation Resistance in Prostate Carcinoma via the Apoptosis Inhibitor TRIAP1.","date":"2019","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30871022","citation_count":27,"is_preprint":false},{"pmid":"27032384","id":"PMC_27032384","title":"TP53 Regulated Inhibitor of Apoptosis 1 (TRIAP1) stable silencing increases late apoptosis by upregulation of caspase 9 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TRIAP1.","date":"2022","source":"BMC urology","url":"https://pubmed.ncbi.nlm.nih.gov/35109849","citation_count":16,"is_preprint":false},{"pmid":"33879126","id":"PMC_33879126","title":"The effect of miR-539 regulating TRIAP1 on the apoptosis, proliferation, migration and invasion of osteosarcoma cells.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33879126","citation_count":15,"is_preprint":false},{"pmid":"32096592","id":"PMC_32096592","title":"TRIAP1 knockdown sensitizes non-small cell lung cancer to ionizing radiation by disrupting redox homeostasis.","date":"2020","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32096592","citation_count":14,"is_preprint":false},{"pmid":"31661694","id":"PMC_31661694","title":"TRIAP1 Inhibition Activates the Cytochrome c/Apaf-1/Caspase-9 Signaling Pathway to Enhance Human Ovarian Cancer Sensitivity to Cisplatin.","date":"2019","source":"Chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/31661694","citation_count":13,"is_preprint":false},{"pmid":"38157298","id":"PMC_38157298","title":"CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38157298","citation_count":12,"is_preprint":false},{"pmid":"35480301","id":"PMC_35480301","title":"miR-107 Inhibits the Proliferation of Gastric Cancer Cells In vivo and In vitro by Targeting TRIAP1.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35480301","citation_count":12,"is_preprint":false},{"pmid":"32764987","id":"PMC_32764987","title":"Upregulation of TRIAP1 by the lncRNA MFI2-AS1/miR-125a-5p Axis Promotes Thyroid Cancer Tumorigenesis.","date":"2020","source":"OncoTargets and 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Society for Experimental Biology and Medicine (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/57624","citation_count":2,"is_preprint":false},{"pmid":"40654025","id":"PMC_40654025","title":"SLMO2 inhibits apoptosis in ovarian cancer cells by modulating mitochondrial function via TRIAP1.","date":"2025","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/40654025","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18986,"output_tokens":4062,"usd":0.058944,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11977,"output_tokens":3993,"usd":0.079855,"stage2_stop_reason":"end_turn"},"total_usd":0.138799,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIAP1 (p53CSV) forms a complex with PRELI in the mitochondrial intermembrane space (IMS) that exerts lipid transfer activity in vitro, supplying phosphatidic acid (PA) for cardiolipin (CL) synthesis in the inner membrane. Loss of TRIAP1 or PRELI impairs CL accumulation, facilitates cytochrome c release, and renders cells vulnerable to apoptosis; survival is rescued by exogenous phosphatidylglycerol.\",\n      \"method\": \"Co-immunoprecipitation, in vitro lipid transfer assay, loss-of-function (siRNA/KO) with cytochrome c release and apoptosis readouts, lipid rescue experiment\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro lipid transfer reconstitution, complex identification, genetic loss-of-function with defined biochemical rescue, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"23931759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mdm35 (the yeast ortholog of TRIAP1) binds Ups1 and Ups2 (PRELI-family proteins) in the mitochondrial IMS, protecting them from proteolytic degradation by Yme1 and Atp23 and ensuring their import, thereby regulating cardiolipin and phosphatidylethanolamine levels in mitochondrial membranes.\",\n      \"method\": \"Yeast genetics, co-immunoprecipitation, protease-sensitivity assays, deletion mutants with lipid quantification\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic deletion with defined lipid phenotypes, protease assays, independently replicated in follow-up studies\",\n      \"pmids\": [\"20657548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ups2-Mdm35 complexes (SLMO2-TRIAP1 in humans) function as phosphatidylserine (PS)-specific lipid transfer proteins in the mitochondrial IMS, enabling PS decarboxylation to phosphatidylethanolamine (PE) by Psd1 at the inner membrane; a recombinant Ups2-Mdm35 fusion protein exhibits PS transfer activity between liposomes in vitro.\",\n      \"method\": \"In vitro liposome lipid transfer assay with recombinant fusion protein, yeast null mutants with radiolabeled PS-to-PE conversion, genetic analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of lipid transfer, confirmed in two independent papers (PMID 27241913, 27354379) with orthogonal methods\",\n      \"pmids\": [\"27241913\", \"27354379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the Ups1-Mdm35-PA complex (yeast ortholog of TRIAP1-PRELI) reveals that Ups1 forms a barrel-like structure with a tunnel-like PA-binding pocket covered by helix α2, while Mdm35 adopts a three-helical clamp-like structure wrapping around Ups1. Hydrophobic residues lining the pocket and helix α2, plus a hydrophilic surface patch near the PA phosphate-binding site, are critical for PA binding and transfer as shown by mutagenesis.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, in vitro PA-binding and transfer assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis and in vitro transfer assays in a single rigorous study\",\n      \"pmids\": [\"26071601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRIAP1 (p53CSV) is a p53 target gene containing a p53-binding site in its second exon. Overexpression protects cells from DNA-damage-induced apoptosis, while siRNA knockdown enhances apoptosis. TRIAP1 interacts with Hsp70 in the cytoplasm, likely inhibiting apoptosome formation via Apaf-1.\",\n      \"method\": \"siRNA knockdown, overexpression, apoptosis assays, co-immunoprecipitation with Hsp70, reporter/binding-site analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — single lab, Co-IP with Hsp70, loss- and gain-of-function with apoptosis readout, p53-binding site identification; mechanism downstream of Hsp70 partially inferred\",\n      \"pmids\": [\"15735003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A genome-wide genetic screen identified TRIAP1 as a specific repressor of p21 (CDKN1A) expression upon p53 activation; TRIAP1 depletion slows cell-cycle progression without broadly affecting PUMA-mediated apoptosis, placing TRIAP1 as a pathway-specific coregulator of the p53 transcriptional program.\",\n      \"method\": \"Genome-wide RNAi screen, targeted siRNA depletion, p21/PUMA expression readouts, cell-cycle analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen followed by targeted validation, single lab, two orthogonal readouts (p21 expression, cell-cycle)\",\n      \"pmids\": [\"23684607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIAP1 knockdown in NPC cells induces mitochondrial fragmentation, membrane potential alteration, and cytochrome c release from mitochondria into the cytosol, enhancing apoptosis; these effects are phenocopied by miR-320b overexpression and reversed by TRIAP1 restoration.\",\n      \"method\": \"siRNA knockdown, overexpression rescue, mitochondrial morphology imaging, membrane potential assay, cytochrome c fractionation, in vivo xenograft\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple cellular assays in single lab, in vivo confirmation, rescue experiment; mechanism limited to cytochrome c release without further biochemical dissection\",\n      \"pmids\": [\"27428374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIAP1 inhibits caspase-9 activation in the cytoplasm (apoptosome-blocking activity); stable overexpression of TRIAP1 in breast cancer cells increases doxorubicin-resistant clone formation, while siRNA knockdown of TRIAP1 in drug-resistant cells impairs growth in the presence of doxorubicin.\",\n      \"method\": \"Stable transfection/overexpression, siRNA, caspase-9 activity assay, colony formation under drug selection\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — caspase assay plus functional drug-resistance readout, replicated concept from Park 2005; mechanistic detail limited in abstract\",\n      \"pmids\": [\"25998939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Stable shRNA-mediated silencing of TRIAP1 in RPMI8226 multiple myeloma cells increases late apoptosis accompanied by upregulation of APAF1 and caspase-9 expression, and activation of caspase-9 and caspase-3/7, establishing that TRIAP1 suppresses the APAF1/caspase-9 apoptosome pathway.\",\n      \"method\": \"Lentiviral shRNA stable knockdown, flow cytometry (annexin V/PI), qRT-PCR for APAF1 and caspase-9, caspase activity assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable genetic knockdown with multiple orthogonal apoptosis readouts; single lab, single cell line\",\n      \"pmids\": [\"27032384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIAP1 is imported into the mitochondrial IMS via the MIA40 oxidative folding relay. In its reduced cytosolic state, TRIAP1 rapidly forms a hydrophobic, alpha-helical, marginally stable molten globule intermediate that biases oxidative folding toward a non-native Cys37-Cys47 kinetic trap. MIA40 accelerates TRIAP1 folding by 30-fold by driving oxidation of the inner disulfide bond (Cys18-Cys37) and then the outer disulfide bond (Cys8-Cys47), yielding the native two-disulfide-bridged structure and bypassing the kinetic trap.\",\n      \"method\": \"NMR, biochemical oxidative folding assays, disulfide-bond mapping, mutagenesis, in vitro MIA40 interaction assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural (NMR) plus in vitro biochemical reconstitution of MIA40-assisted folding with disulfide identification; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39909379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIAP1 upregulation in human cells after nocodazole treatment retains cytochrome c in mitochondria, opposing partial caspase activation caused by prolonged mitotic arrest, thereby enabling escape from the G1 arrest that follows mitotic slippage. Decreasing TRIAP1 re-sensitizes cells to nocodazole.\",\n      \"method\": \"Long-term cell-fate tracking, cytochrome c localization (mitochondrial fractionation/imaging), caspase activation assays, siRNA knockdown and overexpression, proliferation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cytochrome c retention assay, bidirectional manipulation (OE and KD), single lab\",\n      \"pmids\": [\"36917609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Exercise training downregulates CHCHD4, a mitochondrial disulfide relay carrier, which decreases import of TRIAP1 into mitochondria. Reduced mitochondrial TRIAP1 lowers cardiolipin levels and promotes VDAC oligomerization in skeletal muscle, facilitating mtDNA release and activating cGAS-STING/NFKB innate immune signaling, ultimately downregulating MyoD and promoting oxidative slow-twitch fiber formation.\",\n      \"method\": \"Mouse genetic model (CHCHD4 haploinsufficiency), cardiolipin quantification, VDAC oligomerization assay, mtDNA release assay, cGAS-STING/NFKB pathway analysis, skeletal muscle fiber-type characterization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with multiple orthogonal mechanistic readouts; TRIAP1 import dependency on CHCHD4 is central finding but full reconstitution not performed\",\n      \"pmids\": [\"38157298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLMO2 (PRELI) interacts with TRIAP1 in ovarian cancer cells, enhancing mitochondrial membrane potential, reducing ROS, and inhibiting autophagy-dependent apoptosis. Co-expression of SLMO2 and TRIAP1 promotes tumor cell growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation/interaction assay, flow cytometry, western blotting for autophagy markers, mitochondrial membrane potential assay, ROS measurement, xenograft mouse model\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — interaction demonstrated, multiple functional readouts, in vivo confirmation; mechanistic detail on autophagy pathway is limited in the abstract\",\n      \"pmids\": [\"40654025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In colorectal cancer cells, TRIAP1 depletion perturbs mitochondrial ultrastructure and alters endoplasmic reticulum-dependent lipid homeostasis without a major impact on cardiolipin levels or mitochondrial respiratory activity. TRIAP1 depletion also induces a p53-mediated stress response and confers resistance to glutamine deprivation, indicating extramitochondrial roles for TRIAP1 in lipid homeostasis and metabolic stress adaptation.\",\n      \"method\": \"shRNA stable knockdown, electron microscopy (mitochondrial ultrastructure), cardiolipin quantification, metabolomics, p53 pathway reporter assays, glutamine deprivation survival assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab; cardiolipin unchanged finding is a notable negative informing mechanism\",\n      \"pmids\": [\"36387192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIAP1 knockdown in NSCLC cells (A549, H460) decreases expression of multiple antioxidant proteins (TMX1, TMX2, TXN, GLRX2, GLRX3, PRDX3, PRDX4, PRDX6), impairs radiation-induced upregulation of these proteins, and increases intracellular reactive oxygen species, thereby reducing radioresistance.\",\n      \"method\": \"siRNA knockdown, western blotting for antioxidant proteins, ROS measurement, cell viability and apoptosis assays after irradiation\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with protein panel; no direct mechanistic link between TRIAP1 and redox enzyme regulation established\",\n      \"pmids\": [\"32096592\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIAP1 is a small, cysteine-rich mitochondrial IMS protein imported via the MIA40 oxidative folding relay that forms a stable complex with PRELI/SLMO2 and functions as a phosphatidic acid (PA) and phosphatidylserine (PS) lipid transfer protein, supplying substrates for cardiolipin and phosphatidylethanolamine synthesis at the inner membrane; loss of TRIAP1 reduces cardiolipin levels, triggers cytochrome c release, and activates the APAF1/caspase-9 apoptosome, while in the cytoplasm TRIAP1 additionally binds HSP70 to block apoptosome assembly, and its transcription is induced by p53 to promote cell survival under sub-lethal genotoxic stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIAP1 is a small cysteine-rich mitochondrial intermembrane-space (IMS) protein that, together with PRELI-family partners, functions as an intramitochondrial lipid transfer module governing phospholipid biosynthesis and apoptotic priming [#0, #2]. It is imported into the IMS through the MIA40/CHCHD4 oxidative disulfide-relay, which accelerates folding of the reduced cytosolic protein toward its native two-disulfide structure and away from a non-native kinetic trap [#9, #11]. In the IMS TRIAP1 forms a stable complex with PRELI/Ups1 that transfers phosphatidic acid to the inner membrane to support cardiolipin synthesis [#0], while the SLMO2/Ups2-TRIAP1 complex transfers phosphatidylserine to enable its decarboxylation to phosphatidylethanolamine [#2]; the yeast ortholog Mdm35 additionally stabilizes its PRELI-family partners against proteolysis, and crystallography of the Ups1-Mdm35-PA complex defines a barrel-like PA-binding pocket clamped by the Mdm35 three-helix fold [#1, #3]. By maintaining cardiolipin, TRIAP1 restrains cytochrome c release and suppresses the APAF1/caspase-9 apoptosome, so its loss fragments mitochondria, releases cytochrome c, and activates caspase-9/-3 [#0, #6, #8]. TRIAP1 is a p53 target gene that promotes survival under sub-lethal genotoxic stress, binds cytoplasmic HSP70 to block apoptosome assembly, and acts as a pathway-specific repressor of p21 within the p53 program [#4, #5]. Through these activities TRIAP1 confers chemo- and radio-resistance and enables survival following mitotic slippage by retaining cytochrome c in mitochondria [#7, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing TRIAP1 as a p53-inducible survival factor answered how the gene is regulated and connected it to apoptosis suppression via the apoptosome.\",\n      \"evidence\": \"p53-binding-site identification, gain/loss-of-function apoptosis assays, and Hsp70 Co-IP in human cells\",\n      \"pmids\": [\"15735003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism downstream of HSP70 binding only inferred\", \"No structural basis for HSP70 interaction\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Yeast genetics defined Mdm35 (TRIAP1 ortholog) as a chaperone/stabilizer of PRELI-family proteins, linking the protein to mitochondrial phospholipid regulation for the first time.\",\n      \"evidence\": \"Reciprocal Co-IP, protease-sensitivity assays, and deletion mutants with cardiolipin/PE quantification in yeast\",\n      \"pmids\": [\"20657548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lipid transfer activity not yet demonstrated\", \"Human ortholog function not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating TRIAP1-PRELI lipid transfer activity and its requirement for cardiolipin accumulation explained mechanistically how TRIAP1 controls cytochrome c release and apoptotic vulnerability.\",\n      \"evidence\": \"Co-IP, in vitro PA lipid transfer assay, loss-of-function with cytochrome c release readouts, and phosphatidylglycerol rescue in human cells\",\n      \"pmids\": [\"23931759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of transfer in vivo unresolved\", \"Structural basis not defined in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A genome-wide screen revealed TRIAP1 as a pathway-specific repressor of p21, refining its role within the p53 transcriptional program beyond apoptosis suppression.\",\n      \"evidence\": \"Genome-wide RNAi screen with targeted validation, p21/PUMA expression and cell-cycle readouts\",\n      \"pmids\": [\"23684607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of p21 repression unknown\", \"Whether mitochondrial or cytoplasmic TRIAP1 mediates this is unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The Ups1-Mdm35-PA crystal structure provided the atomic architecture of the lipid-binding pocket, converting the functional model into a structural mechanism.\",\n      \"evidence\": \"X-ray crystallography with site-directed mutagenesis and in vitro PA-binding/transfer assays\",\n      \"pmids\": [\"26071601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational changes during lipid loading/unloading not captured\", \"Structure of human TRIAP1 complex not solved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linking TRIAP1 to caspase-9 inhibition and doxorubicin resistance extended its survival function into a chemoresistance context.\",\n      \"evidence\": \"Stable overexpression/siRNA, caspase-9 activity assay, and colony formation under drug selection in breast cancer cells\",\n      \"pmids\": [\"25998939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic detail limited\", \"Direct caspase-9/apoptosome binding not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying Ups2-Mdm35/SLMO2-TRIAP1 as a PS-specific transfer protein enabling PS-to-PE conversion broadened TRIAP1's substrate range and explained its role in PE biosynthesis.\",\n      \"evidence\": \"In vitro liposome transfer with recombinant fusion protein and radiolabeled PS-to-PE conversion in yeast null mutants\",\n      \"pmids\": [\"27241913\", \"27354379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate selectivity determinants between PA and PS partners not fully resolved\", \"In vivo flux control quantification incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Cellular and in vivo loss-of-function studies confirmed that TRIAP1 maintains mitochondrial integrity and represses the APAF1/caspase-9 apoptosome.\",\n      \"evidence\": \"siRNA/shRNA knockdown with rescue, mitochondrial morphology/membrane-potential imaging, cytochrome c fractionation, and qRT-PCR/caspase assays in NPC and myeloma cells plus xenografts\",\n      \"pmids\": [\"27428374\", \"27032384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether effects are solely cardiolipin-dependent not dissected\", \"Direct apoptosome-component binding not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that TRIAP1 depletion alters ER-dependent lipid homeostasis without changing cardiolipin in colorectal cells revealed context-dependent, possibly extramitochondrial, metabolic roles.\",\n      \"evidence\": \"Stable shRNA knockdown with electron microscopy, cardiolipin quantification, metabolomics, p53 reporters, and glutamine-deprivation survival assays\",\n      \"pmids\": [\"36387192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ER lipid homeostasis effect unknown\", \"Reconciliation with cardiolipin-dependent models in other cell types unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies connected TRIAP1 mitochondrial import and abundance to physiological outcomes: cytochrome c retention during mitotic slippage and CHCHD4-dependent control of cardiolipin, VDAC oligomerization, and innate-immune signaling in muscle.\",\n      \"evidence\": \"Cell-fate tracking with cytochrome c localization in human cells, and CHCHD4-haploinsufficient mouse model with cardiolipin/VDAC/mtDNA-release and cGAS-STING readouts\",\n      \"pmids\": [\"36917609\", \"38157298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRIAP1 import dependency on CHCHD4 not reconstituted in vitro\", \"Direct contribution of TRIAP1 versus pathway-wide CHCHD4 effects hard to separate\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapping the MIA40-assisted oxidative folding pathway of TRIAP1 explained how the reduced cytosolic protein attains its native disulfide-bonded IMS structure, and a tumor study reaffirmed the SLMO2-TRIAP1 interaction in promoting survival.\",\n      \"evidence\": \"NMR, disulfide-bond mapping, in vitro MIA40 folding assays; plus Co-IP and functional/xenograft assays in ovarian cancer cells\",\n      \"pmids\": [\"39909379\", \"40654025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo kinetics of TRIAP1 import not measured\", \"How folding state couples to lipid-transfer competence unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIAP1 partitions between its mitochondrial lipid-transfer role and its cytoplasmic apoptosome/HSP70-dependent and p53-coregulatory functions, and whether these are mechanistically coupled, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the human TRIAP1-PRELI or TRIAP1-HSP70 complex\", \"Quantitative determinants of substrate (PA vs PS) selectivity unknown\", \"Cell-type-dependent cardiolipin requirement not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005758\", \"supporting_discovery_ids\": [0, 1, 2, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 6, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"complexes\": [\"TRIAP1-PRELI/SLMO2 lipid transfer complex\"],\n    \"partners\": [\"PRELID1\", \"SLMO2\", \"HSP70\", \"MIA40/CHCHD4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}