Affinage

TRIAP1

TP53-regulated inhibitor of apoptosis 1 · UniProt O43715

Length
76 aa
Mass
8.8 kDa
Annotated
2026-04-28
33 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIAP1 is a small twin CX9C protein of the mitochondrial intermembrane space that functions as an obligate partner of PRELI/SLMO2-family lipid transfer proteins, forming heterodimeric complexes that shuttle phosphatidic acid for cardiolipin synthesis and phosphatidylserine for phosphatidylethanolamine synthesis between mitochondrial membranes (PMID:23931759, PMID:27241913). TRIAP1 is imported via the MIA40 disulfide relay pathway, which catalyzes sequential oxidation of its two disulfide bonds and overcomes a non-native kinetic folding trap (PMID:39909379). Loss of TRIAP1 depletes cardiolipin, promotes VDAC oligomerization and cytochrome c release, and activates the APAF1/caspase-9 apoptosome; conversely, TRIAP1 upregulation retains cytochrome c in mitochondria and suppresses apoptosis during mitotic stress (PMID:23931759, PMID:27032384, PMID:36917609, PMID:38157298). TRIAP1 is also a p53 target gene whose depletion perturbs mitochondrial ultrastructure, ER-dependent lipid homeostasis, and redox balance, linking mitochondrial phospholipid transfer to broader cellular stress responses (PMID:15735003, PMID:36387192, PMID:32096592).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 Medium

    Establishing that TRIAP1 is a p53-inducible anti-apoptotic factor answered how cells modulate death sensitivity after DNA damage, revealing that TRIAP1 interacts with Hsp70 to inhibit APAF1-dependent apoptosis.

    Evidence Co-immunoprecipitation with Hsp70, siRNA knockdown and overexpression in human cancer cells

    PMID:15735003

    Open questions at the time
    • Hsp70 interaction was demonstrated by single Co-IP without reciprocal validation or domain mapping
    • cytosolic vs. mitochondrial pool contributions to anti-apoptotic effect not distinguished
    • mechanism by which TRIAP1-Hsp70 inhibits APAF1 not defined
  2. 2010 High

    Identification of the yeast ortholog Mdm35 as a binding partner of Ups1/Ups2 that protects them from IMS proteases established the conserved chaperoning function of TRIAP1-family proteins within mitochondria, resolving how PRELI-like proteins are stabilized after import.

    Evidence Co-immunoprecipitation, protease sensitivity assays, and genetic deletion in S. cerevisiae

    PMID:20657548

    Open questions at the time
    • Whether human TRIAP1 similarly protects PRELI from degradation was not tested
    • identity of the relevant human IMS proteases unknown
  3. 2013 High

    Reconstitution of phosphatidic acid transfer activity by the TRIAP1–PRELI complex in vitro, coupled with demonstration that loss of either subunit impairs cardiolipin accumulation and sensitizes cells to cytochrome c release, defined the primary molecular function of TRIAP1 as a lipid transfer cofactor essential for cardiolipin biosynthesis.

    Evidence In vitro lipid transfer assay, siRNA knockdown, cytochrome c release assay, phosphatidylglycerol rescue in human cells

    PMID:23931759

    Open questions at the time
    • Whether TRIAP1 contributes catalytically to transfer or solely stabilizes PRELI not resolved
    • structural basis of human complex not determined at this point
  4. 2013 Medium

    A genome-wide RNAi screen placed TRIAP1 as a pathway-specific modulator of p53 signaling by showing that its depletion selectively upregulates p21 while sparing PUMA, revealing an unexpected nuclear/cytoplasmic regulatory role beyond mitochondrial lipid transfer.

    Evidence Genome-wide RNAi screen with p21:PUMA ratio readout, flow cytometry in human cells

    PMID:23684607

    Open questions at the time
    • Mechanism by which TRIAP1 selectively represses p21 not identified
    • whether this reflects a direct transcriptional role or indirect metabolic consequence unknown
  5. 2015 High

    Solving the crystal structure of the Ups1–Mdm35 complex with bound PA revealed how TRIAP1 wraps around its PRELI partner as a three-helical clamp while a hydrophobic tunnel and lid helix in Ups1 accommodate the lipid cargo, providing the structural basis for lipid specificity.

    Evidence X-ray crystallography, mutagenesis, in vitro PA-binding and transfer assays using yeast orthologs

    PMID:26071601

    Open questions at the time
    • Human TRIAP1–PRELI structure not yet solved
    • how membrane association and lipid extraction/insertion occur structurally not resolved
  6. 2016 High

    Demonstration that the SLMO2–TRIAP1 (Ups2–Mdm35) complex transfers phosphatidylserine for PE synthesis expanded the functional repertoire of TRIAP1 beyond cardiolipin metabolism, establishing it as a shared cofactor for distinct lipid transfer specificities dictated by the PRELI-family partner.

    Evidence In vitro liposome-based PS transfer assay, genetic epistasis with MICOS, isotope labeling in yeast and human cells

    PMID:27241913 PMID:27354379

    Open questions at the time
    • Regulation of partner choice (PRELI vs. SLMO2) not understood
    • whether additional PRELI-family partners exist for TRIAP1 not addressed
  7. 2016 Medium

    Stable TRIAP1 knockdown in myeloma cells confirmed that TRIAP1 suppresses the APAF1/caspase-9 intrinsic apoptosis pathway, linking its lipid transfer function to control of the mitochondrial apoptotic cascade.

    Evidence Lentiviral shRNA knockdown, caspase-9/3/7 activity assays, APAF1 qPCR in RPMI8226 cells

    PMID:27032384

    Open questions at the time
    • Whether apoptosis sensitization is solely due to cardiolipin loss or also involves cytosolic TRIAP1 functions not distinguished
    • single cell line
  8. 2020 Medium

    TRIAP1 depletion reduced expression of multiple antioxidant proteins and elevated ROS, uncovering a role for TRIAP1 in redox homeostasis that explains its ability to protect cells against ionizing radiation.

    Evidence siRNA knockdown, western blotting for TMX1/2, TXN, GLRX2/3, PRDX3/4/6, ROS measurement, clonogenic survival in NSCLC cells

    PMID:32096592

    Open questions at the time
    • Whether redox effects are a direct consequence of impaired cardiolipin/PE metabolism or an independent function is unclear
    • single cell type, no rescue experiment reported
  9. 2022 Medium

    Lipidomic and metabolomic profiling of TRIAP1-depleted cells revealed extramitochondrial consequences including altered ER lipid homeostasis and p53-dependent stress responses, broadening the impact of TRIAP1 loss beyond mitochondria.

    Evidence siRNA/shRNA knockdown, electron microscopy, lipidomics, metabolomics, glutamine deprivation assays in colorectal cancer cells

    PMID:36387192

    Open questions at the time
    • Causal chain from mitochondrial lipid deficiency to ER perturbation not established
    • whether extramitochondrial effects reflect a direct ER pool of TRIAP1 unknown
  10. 2023 High

    Placing TRIAP1 downstream of CHCHD4/MIA40-dependent import in exercised muscle showed that reduced TRIAP1 import lowers cardiolipin, promotes VDAC oligomerization and mtDNA release, and activates cGAS-STING signaling to drive slow-twitch fiber formation, establishing an in vivo physiological consequence of TRIAP1 regulation.

    Evidence CHCHD4 haploinsufficient mice, mitochondrial import assays, cardiolipin measurement, VDAC oligomerization assay, cGAS-STING readouts, muscle fiber-type analysis

    PMID:38157298

    Open questions at the time
    • Whether TRIAP1 is the sole CHCHD4 substrate responsible for the phenotype not proven
    • applicability beyond skeletal muscle not tested
  11. 2023 Medium

    TRIAP1 upregulation during prolonged mitotic arrest was shown to retain cytochrome c in mitochondria and suppress partial caspase activation, enabling cells to escape post-mitotic G1 arrest, demonstrating a physiological anti-apoptotic role during mitotic stress.

    Evidence Live-cell imaging, cytochrome c retention and caspase activity assays, overexpression and knockdown in nocodazole-treated human cells

    PMID:36917609

    Open questions at the time
    • Whether cytochrome c retention is mediated through cardiolipin maintenance or an independent mechanism not resolved
    • in vivo relevance during normal mitosis untested
  12. 2025 High

    Biophysical dissection of TRIAP1 folding revealed that MIA40 accelerates its oxidative maturation 30-fold by directing sequential disulfide formation and bypassing a kinetic trap, explaining how TRIAP1 achieves its native structure in the IMS.

    Evidence NMR, in vitro oxidative folding assays, cysteine mutagenesis, MIA40 interaction assays

    PMID:39909379

    Open questions at the time
    • In vivo folding kinetics and whether other IMS factors assist not determined
    • how folding couples to PRELI/SLMO2 complex assembly unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the human TRIAP1–PRELI and TRIAP1–SLMO2 complexes, how TRIAP1 partitions between cytosolic and mitochondrial pools to coordinate anti-apoptotic and lipid transfer functions, and the mechanism by which TRIAP1 influences antioxidant gene expression and ER lipid homeostasis.
  • No human TRIAP1 complex structure solved
  • cytosolic vs. mitochondrial pool regulation mechanism unknown
  • direct vs. indirect effects on antioxidant protein expression not distinguished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0140104 molecular carrier activity 3
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-9609507 Protein localization 2 GO:0005739 mitochondrion 1
Partners
CHCHD4HSPA1APRELID1SLMO2
Complex memberships
TRIAP1-PRELI (Mdm35-Ups1) PA transfer complexTRIAP1-SLMO2 (Mdm35-Ups2) PS transfer complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 TRIAP1 forms a complex with PRELI in the mitochondrial intermembrane space (IMS) and the TRIAP1/PRELI complex 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. Co-immunoprecipitation, in vitro lipid transfer assay, siRNA knockdown, overexpression, cytochrome c release assay, apoptosis assay with exogenous phosphatidylglycerol rescue Cell metabolism High 23931759
2005 TRIAP1 (p53CSV) is a p53 target gene that modulates apoptotic pathways through interaction with Hsp70, which inhibits the activity of apoptosis protease activating factor-1 (Apaf-1). Overexpression protected cells from apoptosis after DNA damage, while siRNA-mediated knockdown enhanced apoptosis. siRNA knockdown, overexpression, co-immunoprecipitation with Hsp70, apoptosis assay, p53-binding site identification in gene Cancer research Medium 15735003
2010 The yeast TRIAP1 ortholog Mdm35 (a twin Cx9C protein) is a novel interaction partner of Ups1 and Ups2 (PRELI-like proteins) in the IMS. Binding to Mdm35 ensures import and protects Ups1/Ups2 against proteolysis by distinct mitochondrial peptidases (Yme1 for Ups2; Yme1 and Atp23 for Ups1), thereby regulating CL and PE accumulation in mitochondria. Co-immunoprecipitation, proteolysis assays, genetic deletion analysis, import assays The EMBO journal High 20657548
2015 Crystal structure of the yeast Ups1-Mdm35 (PRELI-TRIAP1 ortholog) complex with PA bound was solved. Ups1 features a barrel-like structure with a tunnel-like pocket accommodating PA; helix α2 acts as a lid. Mdm35 adopts a three-helical clamp structure wrapping around Ups1. Hydrophobic residues lining the pocket and helix α2 are critical for PA binding and transfer, demonstrated by mutagenesis. X-ray crystallography, in vitro PA-binding assay, lipid transfer assay, site-directed mutagenesis EMBO reports High 26071601
2016 The human SLMO2-TRIAP1 complex (Ups2-Mdm35 in yeast) functions as a phosphatidylserine (PS)-specific lipid transfer protein in the mitochondrial IMS, enabling PE synthesis by the inner membrane decarboxylase Psd1. MICOS deficiency combined with reduced Ups2-Mdm35 PS transfer preserves mitochondrial respiration and cristae formation. Genetic deletion, in vitro lipid transfer assay, mitochondrial fractionation, respiration measurements, electron microscopy The Journal of cell biology High 27241913
2016 A recombinant Ups2-Mdm35 (SLMO2-TRIAP1 ortholog) fusion protein exhibited phospholipid (PS) transfer activity between liposomes in vitro. UPS2/MDM35 null mutations greatly attenuated PS-to-PE conversion in respiration-active yeast, and UPS2 expression was elevated during the diauxic shift. In vitro liposome-based lipid transfer assay, genetic deletion, isotope labeling/PS-to-PE conversion assay The Journal of cell biology High 27354379
2013 In a genome-wide genetic screen, TRIAP1 was identified as a specific repressor of p21 (CDKN1A) expression upon p53 activation; its depletion slows cell-cycle progression without strongly promoting apoptosis, placing TRIAP1 as a pathway-specific coregulator that biases p53 responses toward cell-cycle arrest outcomes. Genome-wide RNAi screen (p21:PUMA ratio readout), siRNA knockdown, flow cytometry cell-cycle analysis Cell reports Medium 23684607
2023 Exercise training downregulates the mitochondrial disulfide relay carrier CHCHD4, which decreases import of TRIAP1 into mitochondria. Reduced mitochondrial TRIAP1 lowers cardiolipin levels and promotes VDAC oligomerization, facilitating mtDNA release that activates cGAS-STING/NF-κB innate immune signaling, downregulates MyoD, and drives formation of oxidative slow-twitch muscle fibers. CHCHD4 haploinsufficiency recapitulates this pathway in mice. CHCHD4 haploinsufficiency mouse model, mitochondrial import assays, cardiolipin measurement, VDAC oligomerization assay, cGAS-STING signaling readouts, muscle fiber-type analysis Cell reports High 38157298
2025 TRIAP1 is imported into the IMS via the MIA40 disulfide relay system. In its reduced cytosolic state, TRIAP1 rapidly populates a hydrophobic, alpha-helical molten globule intermediate that creates a non-native Cys37-Cys47 kinetic trap slowing oxidative folding. MIA40 accelerates TRIAP1 folding 30-fold by driving oxidation of the inner disulfide bond (Cys18-Cys37) and then the outer bond (Cys8-Cys47) to achieve the native two-disulfide-bridged structure, bypassing the kinetic trap. NMR, in vitro oxidative folding assays, mutagenesis of cysteines, MIA40 interaction assays, biophysical characterization of folding intermediates The Journal of biological chemistry High 39909379
2016 Stable knockdown of TRIAP1 in RPMI8226 multiple myeloma cells increased late apoptosis accompanied by upregulation of APAF1 and Caspase-9 expression and increased Caspase-9 and Caspase-3/7 activity, establishing that TRIAP1 functions to suppress the APAF1/Caspase-9 apoptosome pathway. Lentiviral shRNA stable knockdown, flow cytometry (annexin V/PI), caspase activity assays, qPCR Biochimica et biophysica acta Medium 27032384
2023 Triap1 upregulation in human cells surviving nocodazole-induced prolonged mitotic arrest leads to retention of cytochrome c in the mitochondria, opposing partial caspase activation caused by the drug. Increasing Triap1 levels reduced DNA damage and p21 activation, allowing cells to escape G1 arrest and resume proliferation; decreasing Triap1 re-sensitized cells to nocodazole. Long-term live-cell imaging, cytochrome c retention assay, caspase activity assay, overexpression and knockdown, flow cytometry for DNA damage and p21 Cell reports Medium 36917609
2020 TRIAP1 knockdown in NSCLC cells decreased the expression of antioxidant proteins (TMX1, TMX2, TXN, GLRX2, GLRX3, PRDX3, PRDX4, PRDX6) and impaired radiation-induced upregulation of these proteins, increasing intracellular ROS and sensitizing cells to ionizing radiation, identifying TRIAP1 as a regulator of redox homeostasis. siRNA knockdown, western blotting for antioxidant proteins, ROS measurement, clonogenic survival assay, apoptosis assay Thoracic cancer Medium 32096592
2025 SLMO2 (PRELI) physically interacts with TRIAP1 in ovarian cancer cells; this interaction enhances mitochondrial membrane potential, reduces ROS, inhibits autophagy, and suppresses apoptosis, consistent with the SLMO2-TRIAP1 complex regulating mitochondrial function. Co-immunoprecipitation/interaction assay, flow cytometry (membrane potential, ROS), western blot for autophagy proteins, xenograft tumor model Histology and histopathology Medium 40654025
2022 TRIAP1 depletion in colorectal cancer cells perturbs mitochondrial ultrastructure and causes extramitochondrial perturbations including changes in ER-dependent lipid homeostasis and induction of a p53-mediated stress response. Loss of TRIAP1 also confers p53-mediated resistance to glutamine deprivation, demonstrating extramitochondrial functions of TRIAP1. siRNA/shRNA knockdown, electron microscopy, lipidomics, metabolomics, p53 pathway reporter assays, glutamine deprivation survival assays Frontiers in oncology Medium 36387192

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid. Cell metabolism 167 23931759
2010 Regulation of mitochondrial phospholipids by Ups1/PRELI-like proteins depends on proteolysis and Mdm35. The EMBO journal 141 20657548
2016 MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria. The Journal of cell biology 128 27241913
2016 Phosphatidylserine transport by Ups2-Mdm35 in respiration-active mitochondria. The Journal of cell biology 63 27354379
2013 A genetic screen identifies TCF3/E2A and TRIAP1 as pathway-specific regulators of the cellular response to p53 activation. Cell reports 60 23684607
2005 p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway. Cancer research 60 15735003
2016 Overexpression of Mitochondria Mediator Gene TRIAP1 by miR-320b Loss Is Associated with Progression in Nasopharyngeal Carcinoma. PLoS genetics 50 27428374
2015 Structural basis of intramitochondrial phosphatidic acid transport mediated by Ups1-Mdm35 complex. EMBO reports 48 26071601
2009 SAGE analysis highlights the importance of p53csv, ddx5, mapkapk2 and ranbp2 to multiple myeloma tumorigenesis. Cancer letters 44 19171422
2015 Apoptosis inhibitor TRIAP1 is a novel effector of drug resistance. Oncology reports 37 25998939
2017 MicroRNA-18a inhibits ovarian cancer growth via directly targeting TRIAP1 and IPMK. Oncology letters 34 28588697
2021 Circular RNA circPVT1 Contributes to Doxorubicin (DXR) Resistance of Osteosarcoma Cells by Regulating TRIAP1 via miR-137. BioMed research international 28 33981772
2019 Progression-Related Loss of Stromal Caveolin 1 Levels Mediates Radiation Resistance in Prostate Carcinoma via the Apoptosis Inhibitor TRIAP1. Journal of clinical medicine 27 30871022
2016 TP53 Regulated Inhibitor of Apoptosis 1 (TRIAP1) stable silencing increases late apoptosis by upregulation of caspase 9 and APAF1 in RPMI8226 multiple myeloma cell line. Biochimica et biophysica acta 21 27032384
2020 Regulation of Apoptosis and Inflammatory Response in Interleukin-1β-Induced Nucleus Pulposus Cells by miR-125b-5p Via Targeting TRIAP1. Biochemical genetics 17 33123835
2022 PCGEM1 promotes proliferation, migration and invasion in prostate cancer by sponging miR-506 to upregulate TRIAP1. BMC urology 16 35109849
2021 The effect of miR-539 regulating TRIAP1 on the apoptosis, proliferation, migration and invasion of osteosarcoma cells. Cancer cell international 15 33879126
2019 miR-107 targets TRIAP1 to regulate oral squamous cell carcinoma proliferation and migration. International journal of clinical and experimental pathology 15 31934005
2020 TRIAP1 knockdown sensitizes non-small cell lung cancer to ionizing radiation by disrupting redox homeostasis. Thoracic cancer 14 32096592
2019 TRIAP1 Inhibition Activates the Cytochrome c/Apaf-1/Caspase-9 Signaling Pathway to Enhance Human Ovarian Cancer Sensitivity to Cisplatin. Chemotherapy 13 31661694
2022 miR-107 Inhibits the Proliferation of Gastric Cancer Cells In vivo and In vitro by Targeting TRIAP1. Frontiers in genetics 12 35480301
2023 CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise. Cell reports 11 38157298
2020 Upregulation of TRIAP1 by the lncRNA MFI2-AS1/miR-125a-5p Axis Promotes Thyroid Cancer Tumorigenesis. OncoTargets and therapy 11 32764987
2022 Relevance of the TRIAP1/p53 axis in colon cancer cell proliferation and adaptation to glutamine deprivation. Frontiers in oncology 10 36387192
2019 miR-1301/TRIAP1 Axis Participates in Epirubicin-Mediated Anti-Proliferation and Pro-Apoptosis in Osteosarcoma. Yonsei medical journal 10 31433581
2021 Abnormal expression of TRIAP1 and its role in gestational diabetes mellitus-related pancreatic β cells. Experimental and therapeutic medicine 7 33488796
2022 Transcriptomic Analysis Reveals That Granulocyte Colony-Stimulating Factor Trigger a Novel Signaling Pathway (TAF9-P53-TRIAP1-CASP3) to Protect Retinal Ganglion Cells after Ischemic Optic Neuropathy. International journal of molecular sciences 6 35955492
2024 Circular RNA NFIX Functions as an Oncogene in Non-Small Cell Lung Cancer by Modulating the miR-214-3p/TRIAP1 Axis. The clinical respiratory journal 4 39135128
2025 MIA40 circumvents the folding constraints imposed by TRIAP1 function. The Journal of biological chemistry 3 39909379
2023 Triap1 upregulation promotes escape from mitotic-slippage-induced G1 arrest. Cell reports 2 36917609
1976 Biochemical characteristics of rat C-type virus WF-1. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 2 57624
2024 Upregulated microRNA-125b-5p in patients with asthma-COPD overlap mediates oxidative stress and late apoptosis via targeting IL6R/TRIAP1 signaling. Respiratory research 1 38302925
2025 SLMO2 inhibits apoptosis in ovarian cancer cells by modulating mitochondrial function via TRIAP1. Histology and histopathology 0 40654025