{"gene":"TMBIM6","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2004,"finding":"BI-1 (TMBIM6) is an ER-resident protein whose loss selectively sensitizes cells to ER stress-induced apoptosis (thapsigargin, tunicamycin, brefeldin A) but not to mitochondrial or death-receptor apoptosis pathways; protection correlates with inhibition of Bax activation/translocation to mitochondria, preservation of mitochondrial membrane potential, suppression of caspase activation, and reduction of releasable ER Ca2+.","method":"bi-1 knockout mice; cell viability, Bax translocation, mitochondrial membrane potential, caspase activity, and Ca2+ release assays; in vivo stroke and tunicamycin models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal readouts, in vivo validation, replicated across cell types and in vivo models","pmids":["15304216"],"is_preprint":false},{"year":2008,"finding":"BI-1 reduces resting ER Ca2+ ([Ca2+]er) by increasing Ca2+ leakage from the ER, opposing the action of SERCA; BI-1 functions downstream of Bcl-XL in regulating ER Ca2+ homeostasis, and this regulation is independent of Bax/Bak.","method":"ER-targeted cameleon Ca2+ indicator; SERCA co-expression rescue; bi-1-deficient MEFs; bax/bak double-KO cells; Bcl-XL co-expression experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — live-cell Ca2+ imaging with genetic rescue and epistasis experiments using multiple KO backgrounds in one rigorous study","pmids":["18299329"],"is_preprint":false},{"year":2012,"finding":"BI-1 promotes autophagy by reducing steady-state ER Ca2+ levels via IP3Rs, thereby lowering mitochondrial Ca2+ uptake, reducing oxygen consumption and ATP levels, and stimulating autophagy; this function is separable from BI-1's modulation of IRE1 signaling.","method":"BI-1 overexpression and knockdown; bi-1-/- mice (basal autophagy); IP3R epistasis; oxygen consumption and ATP measurements; tumor xenograft growth","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mice, multiple orthogonal assays (Ca2+, bioenergetics, autophagy flux, xenograft), IP3R epistasis in single study","pmids":["22588718"],"is_preprint":false},{"year":2010,"finding":"BAR (bifunctional apoptosis regulator) is an ER-resident RING-type E3 ubiquitin ligase that interacts with BI-1 and promotes its proteasomal degradation; BAR knockdown stabilizes BI-1 protein and enhances inhibition of IRE1 signaling during ER stress; endogenous BAR levels decline under prolonged ER stress.","method":"Co-IP; RING-domain mutant BAR; siRNA knockdown; proteasome inhibitor; IRE1 activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction, dominant-negative RING mutant, and functional IRE1 readout in a single focused study","pmids":["21068390"],"is_preprint":false},{"year":2012,"finding":"BI-1 has a six-transmembrane topology (not seven) with a putative re-entrant loop at the C-terminus and both N- and C-termini in the cytosol; mutation of charged C-terminal residues of hGAAP (a TMBIM family member used as topology model) abolishes anti-apoptotic function.","method":"Topology mapping by selective permeabilization and epitope-tag accessibility; mutagenesis of charged C-terminal residues; functional anti-apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic topology mapping with orthogonal permeabilization methods and mutagenesis-function link in a single study","pmids":["22418439"],"is_preprint":false},{"year":2020,"finding":"TMBIM6 physically associates with mTORC2 and promotes mTORC2 assembly and activation; ER Ca2+ leak from TMBIM6 affects mTORC2 association with ribosomes. The compound BIA prevents TMBIM6 binding to mTORC2 and inhibits mTORC2 activity and tumor growth.","method":"Co-IP of TMBIM6 with mTORC2 components; TMBIM6 KO/KD; BIA antagonist treatment; Ca2+ measurements; glycolysis and lipid synthesis assays; cancer xenograft models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, genetic KO, pharmacological inhibitor, multiple downstream pathway readouts, and in vivo xenograft validation in one study","pmids":["32782388"],"is_preprint":false},{"year":2020,"finding":"TMBIM6-derived ER Ca2+ efflux elevates lysosomal Ca2+ levels independently of IP3Rs; under nutrient starvation or mTOR inhibition, TMBIM6 promotes local Ca2+ release through lysosomal MCOLN1/TRPML1 channels, activating PPP3/calcineurin and TFEB nuclear translocation to induce autophagy and lysosome biogenesis.","method":"CEPIA Ca2+ indicators in ER and lysosomes; TMBIM6 KO MEFs and tmbim6-/- mice; MCOLN1 pharmacology (ML-SA1); calcineurin inhibitor; TFEB nuclear translocation imaging; autophagy flux in vivo","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — organelle-specific Ca2+ sensors, genetic KO in cells and mice, pharmacological dissection of MCOLN1 and calcineurin, multiple orthogonal readouts","pmids":["32167007"],"is_preprint":false},{"year":2023,"finding":"TMBIM6 interacts with VDAC1 and prevents its oligomerization, thereby restraining mitochondrial Ca2+ uptake and maintaining mitochondrial quality control; TMBIM6CKO exacerbates LPS-induced septic cardiomyopathy while TMBIM6TG is protective.","method":"Co-IP; mutant TMBIM6 plasmid transfection; molecular docking; TMBIM6CKO and TMBIM6TG mice; LPS sepsis model; mitochondrial respiration, fission, mitophagy, and Ca2+ assays","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, molecular docking, and in vivo genetic models with multiple functional readouts in one study","pmids":["36603706"],"is_preprint":false},{"year":2020,"finding":"DNA-PKcs physically interacts with BI-1 and promotes its degradation (post-transcriptionally, without affecting BI-1 transcription); DNA-PKcs knockout stabilizes BI-1, protecting mitochondria from IR injury; double knockout of DNA-PKcs and BI-1 abolishes cardioprotection, placing BI-1 downstream of DNA-PKcs.","method":"DNA-PKcsCKO mice; double KO (DNA-PKcs + BI-1); Co-IP; phosphorylation assays; cardiac IR model; mitochondrial fission, mPTP, mitophagy, and Bax-mediated apoptosis assays","journal":"Basic research in cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Co-IP, genetic epistasis via double KO, in vivo cardiac IR model, multiple orthogonal mitochondrial readouts","pmids":["31919590"],"is_preprint":false},{"year":2006,"finding":"BI-1 provides endogenous cytoprotection of liver and kidney from ER stress and ischemia-reperfusion injury; bi-1-/- mice show increased histological injury, hepatocyte death, caspase activity, and elevated IRE1, ATF6, CHOP, and spliced XBP-1 after hepatic or renal IR, and bi-1 mRNA is induced by IR in wild-type liver.","method":"bi-1 knockout mice; hepatic and renal artery occlusion IR models; TUNEL, caspase assays, serum transaminases, immunoblot for UPR markers","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in two organ systems with multiple orthogonal readouts and in vivo disease model, independent replication of ER stress protection concept","pmids":["16478805"],"is_preprint":false},{"year":2010,"finding":"BI-1 modulates the unfolded protein response: it directly interacts with IRE1 and inhibits IRE1 endonuclease activity; BI-1 transgenic neurons and mice show reduced UPR marker induction (CHOP) and reduced brain lesion volume after stroke and traumatic brain injury.","method":"BI-1 transgenic mice with neuron-specific promoter; MCAO stroke and controlled cortical impact TBI models; UPR marker immunoblot; primary cortical neuron ER stress assays","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic OE with in vivo disease models and UPR marker readouts; IRE1 interaction inferred from prior published Co-IP (not re-demonstrated here), single lab","pmids":["21075086"],"is_preprint":false},{"year":2019,"finding":"BI-1 overexpression protects against neonatal hypoxic-ischemic brain injury by inhibiting the IRE1α branch of the UPR and in part the PERK branch; silencing BI-1 or activating IRE1α with a CRISPR activation plasmid reverses protection.","method":"Adenoviral TMBIM6 overexpression in vivo (rat pup HI model) and in vitro (OGD); CRISPR activation of IRE1α; siRNA silencing; infarct area, neurodegeneration, and long-term behavioral outcomes","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — viral OE plus epistasis via CRISPR/siRNA, in vivo and in vitro confirmation, single lab","pmids":["31636086"],"is_preprint":false},{"year":2019,"finding":"BI-1 disrupts the NPR-CYP2E1 complex and upregulates Nrf-2/HO-1, reducing ER stress-induced ROS production; silencing either BI-1 or Nrf-2 reverses protection after neonatal HI injury.","method":"Adenoviral TMBIM6 overexpression; siRNA silencing of BI-1 and Nrf-2; NPR-CYP2E1 complex analysis by Co-IP; DHE ROS staining; HO-1 activity; in vivo rat HI model","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for NPR-CYP complex, siRNA epistasis, in vivo model; single lab, mechanistic chain partially inferred","pmids":["31472686"],"is_preprint":false},{"year":2016,"finding":"BI-1 protects against obesity-induced hepatic insulin resistance by reducing CYP2E1 activity and CYP2E1-dependent ROS production; BI-1 KO mice fed a high-fat diet showed increased CYP2E1 activity and ER stress, while stable BI-1 expression in HepG2 cells reduced palmitate-induced ER stress and CYP2E1-dependent ROS, preserving insulin signaling.","method":"bi-1 KO mice on high-fat diet; stable TMBIM6 expression in HepG2; CYP2E1 activity assay; ROS measurement; glucose/insulin tolerance tests; ER stress markers by immunoblot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and stable OE with enzyme activity assay and functional metabolic readouts; single lab","pmids":["27576594"],"is_preprint":false},{"year":2011,"finding":"Klf10 transcription factor directly binds the BI-1 promoter and suppresses BI-1 transcription; estrogen-induced Klf10 reduces BI-1 expression, causing cytosolic Ca2+ increase and apoptosis in breast cancer cells. Mutation of the Klf10 binding element in the BI-1 promoter reverses estrogen-induced repression.","method":"ChIP-chip; BI-1 promoter reporter assays; EMSA; siRNA-Klf10; Ca2+ imaging; apoptosis assays","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, EMSA, promoter mutagenesis, and functional Ca2+/apoptosis readouts; single lab","pmids":["21262377"],"is_preprint":false},{"year":2019,"finding":"Sp1 is the essential transcription factor for basal TMBIM6 promoter activity (core promoter -133/+30 bp); PKC activation (via PKCι, PKCε, PKCδ) enhances TMBIM6 expression by promoting nuclear translocation of Sp1.","method":"Reporter gene assays with promoter deletions and mutations; EMSA; supershift assay; ChIP; siRNA against Sp1; mithramycin-A inhibition; PKC active-mutant overexpression; nuclear fractionation","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal promoter assays (EMSA, ChIP, reporter mutations, supershift), single lab","pmids":["31336725"],"is_preprint":false},{"year":2021,"finding":"RBM15-mediated m6A modification of TMBIM6 mRNA enhances TMBIM6 mRNA stability in an IGF2BP3-dependent manner in laryngeal squamous cell carcinoma.","method":"m6A microarray; MeRIP-seq; RIP assay; RNase MazF methylation site mapping; actinomycin D mRNA stability assay; RBM15 knockdown/overexpression","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq, RIP, RNase MazF site mapping, and mRNA stability assay; single lab","pmids":["33637103"],"is_preprint":false},{"year":2021,"finding":"TMBIM6 deficiency leads to redox-mediated posttranslational modifications of IRE1α (S-nitrosylation and sulfonation); sulfonation of IRE1α enhances RIDD activity causing TMBIM6 mRNA decay (creating a feedback loop), while S-nitrosylation inhibits XBP1 splicing promoting cell death in aging liver.","method":"TMBIM6-/- mice and human aging liver samples; S-nitrosylation and sulfonation detection; IRE1α endonuclease (RIDD and XBP1 splicing) activity assays; TMBIM6 rescue in KO old mice and stable hepatic cell lines","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical PTM detection combined with genetic KO/rescue and functional IRE1α activity assays; single lab","pmids":["34562874"],"is_preprint":false},{"year":1998,"finding":"Human TEGT/TMBIM6 protein localizes primarily to the endoplasmic reticulum; in vitro translation requires microsomes for efficient synthesis, and the protein shows no signal peptide cleavage, N-linked, or O-linked glycosylation; it tends to self-aggregate due to hydrophobicity.","method":"Immunofluorescence of HA-tagged hTEGT; in vitro translation with/without microsomes; SDS-PAGE and glycosylation analysis","journal":"Molecular membrane biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization experiment with functional implication (ER targeting for translation) and biochemical characterization; single early study","pmids":["10087504"],"is_preprint":false},{"year":2007,"finding":"BI-1 deficiency accelerates liver regeneration after partial hepatectomy: bi-1-/- hepatocytes enter the cell cycle faster, with earlier cyclin D1/D3/Cdk2/Cdk4 induction, faster Rb hyperphosphorylation, p27Kip1 degradation, and accelerated calcineurin-dependent NFAT1 nuclear translocation, linking BI-1's ER Ca2+ regulation to cell proliferation control.","method":"Partial hepatectomy in bi-1-/- vs wild-type mice; BrdU incorporation; cyclin/Cdk immunoblot; Rb phosphorylation; p27 levels; NFAT1 nuclear translocation; calcineurin substrate dephosphorylation","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO model with multiple cell-cycle readouts and Ca2+/calcineurin mechanistic link; single lab","pmids":["17308082"],"is_preprint":false},{"year":2012,"finding":"BI-1 overexpression activates ERK1/2, which suppresses mitochondria-derived ROS production; ERK or BI-1 siRNA knockdown reverses the anti-apoptotic and anti-ROS effects, placing ERK1/2 activation downstream of BI-1 in stress protection.","method":"BI-1 overexpression in cells; ERK siRNA knockdown; BI-1 siRNA; ROS measurement; apoptosis assays; MEFs from BI-1 transgenic mice","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA epistasis with ROS and apoptosis functional readouts, confirmed in transgenic MEFs; single lab","pmids":["22309999"],"is_preprint":false},{"year":2015,"finding":"TMBIM6 enhances autophagy and protects against CsA-induced nephrotoxicity by activating lysosomal function; TMBIM6-expressing cells maintain AMPK phosphorylation, suppress mTORC1, and upregulate TFEB (lysosome biogenesis factor); tmbim6-/- mice show impaired autophagic clearance and increased CsA kidney injury.","method":"TMBIM6-expressing HK-2 cells; tmbim6-/- mice; CsA treatment; autophagosome and lysosome markers; AMPK/mTORC1/TFEB immunoblot; lysosomal activity assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mice and stable OE cells with multiple signaling and functional readouts; single lab","pmids":["26305401"],"is_preprint":false},{"year":2018,"finding":"TMBIM6 protects against cisplatin-induced testicular toxicity by inducing HO-1 (via Akt-Nrf2 axis) and enhancing ER folding capacity, reducing PDI carbonylation and oxidative stress; TMBIM6 KO mice show loss of protection, rescued by lentiviral TMBIM6 re-expression in testis.","method":"Tmbim6 KO and Tmbim6-overexpressing TM3 Leydig cells; lentiviral testicular rescue; HO-1 activity and Nrf2 immunoblot; PDI carbonylation; ROS; testosterone synthesis enzyme levels","journal":"Human reproduction (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with lentiviral rescue, multiple biochemical readouts; single lab","pmids":["29309588"],"is_preprint":false},{"year":2011,"finding":"BI-1 overexpression leads to extracellular acidification via altered mitochondrial metabolism, promoting monocarboxylate transporter (MCT) upregulation downstream of NHE activation; MCT inhibition with lonidamine blocks extracellular acidification and suppresses cancer cell migration, invasion, and MMP2/9 activity in BI-1-overexpressing cells.","method":"pH measurement; NHE and MCT inhibitors; siRNA; MMP activity assays; migration/invasion assays in BI-1-overexpressing HT1080 cells","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological inhibitors only, mechanistic chain largely inferred from inhibitor effects","pmids":["21537843"],"is_preprint":false},{"year":2014,"finding":"BI-1 overexpression sensitizes cells to Fas-induced death through a mechanism involving intracellular pH drop, BI-1 oligomerization, mitochondrial Ca2+ accumulation, and significant inhibition of sodium-hydrogen exchanger (NHE) activity.","method":"BI-1-overexpressing HT1080 cells; Fas treatment; cytosolic pH measurement; NHE inhibitor (EIPA) and siRNA; Ca2+ accumulation assay; caspase-3 assay","journal":"BMB reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological and siRNA approach, mechanistic details partially inferred","pmids":["24314142"],"is_preprint":false},{"year":2023,"finding":"TMBIM6 regulates mitochondrial Ca2+ homeostasis and mitochondrial quality surveillance (MQS) through a TMBIM6-VDAC1 interaction; hypoxia-induced TMBIM6 blockade over-activates VDAC1 (major mitochondrial Ca2+ uptake route), causing Ca2+ overload; ZSHX decoction increases TMBIM6 expression, inhibits VDAC1-mediated Ca2+ overload, and normalizes MQS.","method":"TMBIM6CKO, TMBIM6TG, and VDAC1TG mice; ischemic myocardial injury model; Ca2+ and mitochondrial function assays","journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic mouse models with functional readouts, but mechanistic TMBIM6-VDAC1 interaction evidence here is indirect (supported more directly by PMID 36603706)","pmids":["38870748"],"is_preprint":false},{"year":2023,"finding":"TMBIM6 serves as a negative regulator of osteoclastogenesis by scavenging ROS and preventing NF-κB p65 nuclear localization; Tmbim6-KO mice show an osteoporotic phenotype; TMBIM6 controls redox regulation via NRF2 signaling.","method":"Tmbim6-KO mice; osteoclast differentiation assays; TRAP staining; ROS scavenging assays; p65 nuclear localization; N-acetylcysteine rescue; transcriptome analysis; NRF2 pathway immunoblot","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo and in vitro with multiple mechanistic readouts including epistasis via antioxidant rescue; single lab","pmids":["37399733"],"is_preprint":false},{"year":2024,"finding":"TMBIM6 agonism in cancer cells activates cytosolic Ca2+ and ROS, induces lysosome biogenesis, and triggers paraptosis via ERAD II mechanisms; this occurs independent of canonical p38 MAPK, JNK, ERK, UPR, autophagy, proteasomes, or Caspase-9 pathways; TMBIM6 undergoes conformational changes upon intracellular environment (ICE) change that dictate its function.","method":"TMBIM6 agonist treatment; pathway inhibitors; Ca2+ and ROS measurements; lysosome biogenesis assays; xenograft models; paraptosis morphological analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological agonism with multiple pathway inhibitors, Ca2+/ROS readouts, and in vivo xenograft; single lab, mechanistic chain partially by exclusion","pmids":["39609612"],"is_preprint":false},{"year":2026,"finding":"TMBIM6 directly binds IRE1α and inhibits its activation in dopaminergic neurons; α-synuclein preformed fibrils disrupt the TMBIM6-IRE1α complex; pharmacological or genetic IRE1α inhibition prevents cell death in TMBIM6-deficient cells; AAV-mediated TMBIM6 overexpression in mice improves motor function and dopaminergic neuron survival in Parkinson's disease models.","method":"Co-IP of TMBIM6-IRE1α; TMBIM6 KD/OE in DAergic cells and primary neurons; aSyn PFF treatment; IRE1α inhibitor rescue; Drosophila rotenone model; AAV mouse overexpression; single-cell RNA-seq","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, pharmacological epistasis, multiple in vivo models (Drosophila and mouse AAV); single lab, published 2026","pmids":["41932887"],"is_preprint":false},{"year":2025,"finding":"CSDE1 (an RNA-binding protein) competes with AGO2 for binding to TMBIM6 mRNA, protecting it from miR-20a-5p-mediated silencing and enhancing TMBIM6 protein levels post-transcriptionally without affecting mRNA abundance; an RNA-binding mutant of CSDE1 fails to compete with AGO2.","method":"RIP of CSDE1 and AGO2 on TMBIM6 mRNA; RNA-binding mutant CSDE1; miR-20a-5p overexpression; TMBIM6 protein and mRNA measurement","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP demonstrating competitive binding, mutagenesis of CSDE1 RNA-binding domain, functional protein readout; single lab","pmids":["41093770"],"is_preprint":false},{"year":2022,"finding":"METTL3-mediated m6A modification of TMBIM6 mRNA, read by YTHDF2, decreases TMBIM6 mRNA stability and expression in preeclamptic trophoblasts; YTHDF2 knockdown increases TMBIM6 mRNA stability; TMBIM6 overexpression counteracts METTL3-driven ER stress and trophoblast dysfunction.","method":"MeRIP-qPCR; shRNA knockdown of METTL3 and YTHDF2; mRNA stability assay; TMBIM6 overexpression rescue; ER stress and apoptosis assays in HTR-8/SVneo cells; preeclamptic rat model","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP and mRNA stability assay plus genetic rescue; single lab","pmids":["36747144"],"is_preprint":false},{"year":2025,"finding":"TCF3 transcription factor directly binds the TMBIM6 promoter and transcriptionally activates TMBIM6 expression; TMBIM6 overexpression reduces intracellular Ca2+ and promotes ferroptosis resistance in bladder cancer, while TMBIM6 knockdown reverses TCF3-mediated effects.","method":"ChIP and luciferase assays for TCF3/TMBIM6 promoter interaction; TMBIM6 OE and KD; BAPTA-AM Ca2+ chelation; ferroptosis markers (GPX4, SLC7A11, MDA, Fe2+, lipid ROS); Erastin treatment; xenograft model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase for direct transcriptional activation, Ca2+ chelation epistasis, in vivo xenograft; single lab","pmids":["40610429"],"is_preprint":false}],"current_model":"TMBIM6/BI-1 is an evolutionarily conserved, six-transmembrane ER-resident protein that functions as a Ca2+ leak channel, reducing resting ER [Ca2+] and thereby regulating downstream Ca2+-dependent processes including: inhibition of Bax activation and ER stress-induced apoptosis (acting downstream of Bcl-XL and upstream of mitochondrial apoptosis), direct inhibition of IRE1α endonuclease activity to modulate UPR signaling, promotion of autophagy via IP3R-dependent lowering of mitochondrial bioenergetics and via lysosomal MCOLN1/calcineurin/TFEB activation, interaction with and prevention of VDAC1 oligomerization to maintain mitochondrial Ca2+ homeostasis, assembly with mTORC2 to promote its activation and downstream AKT/metabolic signaling in cancer, and transcriptional regulation by Sp1/PKC and post-translational regulation by the E3 ligase BAR; its expression is also post-transcriptionally controlled by m6A modification (written by RBM15/METTL3, read by IGF2BP3/YTHDF2) and by competition between CSDE1 and AGO2/miRNAs for TMBIM6 mRNA."},"narrative":{"mechanistic_narrative":"TMBIM6 (BI-1/TEGT) is an endoplasmic reticulum-resident, six-transmembrane protein that governs cell fate under stress by acting as a Ca2+ leak channel that lowers resting ER Ca2+, thereby tuning a broad network of Ca2+-dependent survival, autophagy, and metabolic responses [PMID:15304216, PMID:18299329, PMID:22418439, PMID:10087504]. Its loss selectively sensitizes cells to ER stress-induced apoptosis by permitting Bax activation and mitochondrial damage, an anti-apoptotic activity that operates downstream of Bcl-XL and independently of Bax/Bak in setting ER Ca2+ tone [PMID:15304216, PMID:18299329]. A central effector arm is the unfolded protein response: TMBIM6 directly binds IRE1α and restrains its endonuclease activity, limiting UPR marker induction and protecting neurons and liver in stroke, hypoxic-ischemic, and aging models [PMID:21075086, PMID:31636086, PMID:41932887]; under TMBIM6 deficiency, redox-driven modifications of IRE1α (S-nitrosylation and sulfonation) further dysregulate XBP1 splicing and RIDD, the latter degrading TMBIM6 mRNA in a feedback loop [PMID:34562874]. TMBIM6-derived ER Ca2+ efflux also drives autophagy through two routes: an IP3R-dependent lowering of mitochondrial Ca2+ uptake and bioenergetics, and an IP3R-independent elevation of lysosomal Ca2+ via MCOLN1 that activates calcineurin and TFEB to promote lysosome biogenesis [PMID:22588718, PMID:32167007, PMID:26305401]. At the mitochondrial interface, TMBIM6 binds VDAC1 and prevents its oligomerization to restrain mitochondrial Ca2+ overload and preserve mitochondrial quality control [PMID:36603706]. Beyond stress protection, TMBIM6 associates with mTORC2 to promote its assembly and downstream metabolic signaling in cancer [PMID:32782388], and limits oxidative stress through Nrf2/HO-1 and CYP2E1-directed mechanisms across hepatic, testicular, and bone contexts [PMID:27576594, PMID:29309588, PMID:37399733]. TMBIM6 abundance is controlled at multiple levels: transcriptionally by Sp1/PKC, Klf10, TCF3, and TGF-responsive inputs [PMID:21262377, PMID:31336725, PMID:40610429], post-transcriptionally by opposing m6A readers and by CSDE1/AGO2 competition for its mRNA [PMID:33637103, PMID:41093770, PMID:36747144], and post-translationally by E3 ligase BAR and by DNA-PKcs-promoted degradation [PMID:21068390, PMID:31919590].","teleology":[{"year":2004,"claim":"Established TMBIM6/BI-1 as an ER-localized, selective inhibitor of ER stress-induced apoptosis, defining the core question of how an ER protein blocks the mitochondrial death step.","evidence":"bi-1 knockout mice with Bax translocation, mitochondrial potential, caspase, and ER Ca2+ readouts plus in vivo stroke/tunicamycin models","pmids":["15304216"],"confidence":"High","gaps":["Did not define the channel mechanism linking BI-1 to reduced ER Ca2+","Direct molecular partners not identified"]},{"year":2006,"claim":"Showed endogenous BI-1 protects organs from ischemia-reperfusion injury, extending the apoptosis findings to in vivo physiological stress and linking loss to UPR marker elevation.","evidence":"bi-1 knockout mice in hepatic and renal IR with UPR marker immunoblot and injury readouts","pmids":["16478805"],"confidence":"High","gaps":["Mechanism connecting BI-1 to specific UPR branches not resolved here"]},{"year":2008,"claim":"Defined the biochemical basis of protection: BI-1 lowers resting ER Ca2+ by promoting Ca2+ leak downstream of Bcl-XL and independently of Bax/Bak.","evidence":"ER-targeted cameleon imaging with SERCA rescue and epistasis in multiple KO backgrounds","pmids":["18299329"],"confidence":"High","gaps":["Direct demonstration of channel pore activity by reconstitution not shown","Structural basis of Ca2+ conduction unresolved"]},{"year":2010,"claim":"Identified two distinct regulatory nodes: direct inhibition of IRE1 endonuclease activity (UPR control) and BAR-mediated proteasomal degradation (protein turnover control).","evidence":"BI-1 transgenic mice in stroke/TBI for IRE1/UPR readouts; Co-IP, RING-mutant, and proteasome inhibition for BAR","pmids":["21075086","21068390"],"confidence":"Medium","gaps":["IRE1 interaction in the transgenic study inferred from prior Co-IP, not re-demonstrated","Whether BAR degradation is stress-regulated in vivo not established"]},{"year":2012,"claim":"Connected ER Ca2+ regulation to downstream physiology, showing BI-1 promotes autophagy via IP3R-dependent lowering of mitochondrial bioenergetics, and activates ERK1/2 to suppress ROS.","evidence":"bi-1-/- mice and overexpression with IP3R epistasis, bioenergetics, autophagy flux, xenografts; ERK siRNA epistasis with ROS/apoptosis readouts","pmids":["22588718","22309999"],"confidence":"High","gaps":["Autophagy and IRE1 functions stated to be separable but molecular branch point undefined","ERK activation mechanism downstream of BI-1 not detailed"]},{"year":2012,"claim":"Resolved the membrane topology as six transmembrane domains with cytosolic termini, providing the structural framework for the Ca2+ leak and anti-apoptotic activity.","evidence":"Topology mapping by selective permeabilization and epitope accessibility with charged-residue mutagenesis","pmids":["22418439"],"confidence":"High","gaps":["High-resolution structure of the channel not determined","Topology partly modeled via TMBIM family member hGAAP"]},{"year":2019,"claim":"Mapped transcriptional control of TMBIM6, establishing Sp1/PKC as basal activators and Klf10 and CYP2E1/Nrf2 axes as context-specific modulators of expression and redox protection.","evidence":"Promoter reporter, EMSA, ChIP, supershift for Sp1; adenoviral OE and siRNA epistasis in HI and metabolic models for CYP2E1/Nrf2","pmids":["31336725","31472686","31636086","27576594","21262377"],"confidence":"Medium","gaps":["Integration of multiple transcription factors in a single cell type untested","Redox mechanistic chains partly inferred from inhibitor/siRNA effects"]},{"year":2020,"claim":"Expanded the interactome beyond apoptosis, showing TMBIM6 binds mTORC2 to promote its assembly and activation, and drives lysosomal autophagy via an IP3R-independent MCOLN1/calcineurin/TFEB route.","evidence":"Reciprocal Co-IP, KO/KD, BIA antagonist, xenografts for mTORC2; organelle-specific Ca2+ sensors, KO mice, and MCOLN1/calcineurin pharmacology for the lysosomal axis","pmids":["32782388","32167007"],"confidence":"High","gaps":["Structural basis of TMBIM6-mTORC2 association undefined","How ER Ca2+ leak is locally directed to lysosomes vs mitochondria unresolved"]},{"year":2020,"claim":"Identified DNA-PKcs as a post-transcriptional negative regulator that promotes BI-1 degradation, placing BI-1 downstream of DNA-PKcs in mitochondrial cardioprotection.","evidence":"DNA-PKcs CKO and DNA-PKcs/BI-1 double KO mice with Co-IP and cardiac IR mitochondrial readouts","pmids":["31919590"],"confidence":"High","gaps":["Whether DNA-PKcs phosphorylates BI-1 directly to trigger degradation not pinned down"]},{"year":2021,"claim":"Revealed reciprocal regulation between TMBIM6 and IRE1α redox state, with TMBIM6 loss enabling IRE1α sulfonation/S-nitrosylation that feeds back to degrade TMBIM6 mRNA, and defined m6A control of TMBIM6 abundance.","evidence":"TMBIM6-/- mice and aging liver with PTM detection and IRE1α activity assays; MeRIP-seq, RIP, and mRNA stability for RBM15/IGF2BP3","pmids":["34562874","33637103"],"confidence":"Medium","gaps":["Direct causal ordering of IRE1α PTMs versus TMBIM6 loss not fully separated","m6A control demonstrated in a single cancer context"]},{"year":2023,"claim":"Established the TMBIM6-VDAC1 interaction as the mechanism preventing mitochondrial Ca2+ overload, linking TMBIM6 to mitochondrial quality control in cardiac disease.","evidence":"Co-IP, mutagenesis, molecular docking, and CKO/TG mouse models in septic and ischemic cardiomyopathy","pmids":["36603706","38870748"],"confidence":"High","gaps":["Structural interface of the TMBIM6-VDAC1 contact not solved","ZSHX decoction effect on the interaction is indirect"]},{"year":2024,"claim":"Demonstrated that pharmacological TMBIM6 agonism flips its survival role to a death-promoting one, inducing Ca2+/ROS-driven paraptosis via ERAD II, indicating conformation-dependent functional switching.","evidence":"TMBIM6 agonist with pathway inhibitor panel, Ca2+/ROS and lysosome readouts, paraptosis morphology, and xenografts","pmids":["39609612"],"confidence":"Medium","gaps":["Conformational change model inferred, not directly visualized","Death mechanism defined largely by exclusion of canonical pathways"]},{"year":2025,"claim":"Extended regulatory control to competitive RNA-binding and disease-specific transcriptional activation, defining CSDE1/AGO2 competition and TCF3/m6A inputs that set TMBIM6 levels and influence ferroptosis resistance.","evidence":"RIP and CSDE1 RNA-binding mutant for AGO2 competition; ChIP/luciferase for TCF3; MeRIP and YTHDF2 knockdown for m6A; ferroptosis and Ca2+ chelation readouts","pmids":["41093770","40610429","36747144"],"confidence":"Medium","gaps":["Whether these regulatory layers co-occur in the same cell type untested","Single-lab findings per regulatory mechanism"]},{"year":2026,"claim":"Demonstrated a neuroprotective TMBIM6-IRE1α axis in dopaminergic neurons, with α-synuclein fibrils disrupting the complex, connecting TMBIM6's UPR control to Parkinson's disease models.","evidence":"Co-IP, KD/OE in DAergic cells, IRE1α inhibitor rescue, Drosophila and AAV mouse PD models, single-cell RNA-seq","pmids":["41932887"],"confidence":"Medium","gaps":["How αSyn fibrils mechanistically disrupt the complex undefined","Single lab"]},{"year":null,"claim":"How TMBIM6 conducts Ca2+ at atomic resolution and how a single ER channel coordinately partitions its ER-mitochondria-lysosome Ca2+ output to select among apoptosis, autophagy, and metabolic outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution channel structure","Mechanism that routes Ca2+ leak to specific downstream effectors unknown","Determinants of the survival-versus-death functional switch unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,5,7,28]},{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[13,22,26]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,18,4]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,10,17]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,27]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,6,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5]}],"complexes":["mTORC2"],"partners":["IRE1Α","VDAC1","BAR","DNA-PKCS","BCL-XL","MTORC2","CSDE1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P55061","full_name":"Bax inhibitor 1","aliases":["Testis-enhanced gene transcript protein","Transmembrane BAX inhibitor motif-containing protein 6"],"length_aa":237,"mass_kda":26.5,"function":"Endoplasmic reticulum (ER)-resident protein that confers cellular protection as an anti-apoptotic protein by limiting multiple stress-inducing pathways surrounding the endoplasmic reticulum and mitochondria (PubMed:21075086, PubMed:21068390). Inhibits the activities of the key sensor for the endoplasmic reticulum unfolded protein response IRE1alpha/ERN1 both directly and by blocking BAX/BAK binding (PubMed:19328063). Modulates ER calcium homeostasis by acting as a calcium-leak channel (PubMed:22128171). 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protection correlates with inhibition of Bax activation/translocation to mitochondria, preservation of mitochondrial membrane potential, suppression of caspase activation, and reduction of releasable ER Ca2+.\",\n      \"method\": \"bi-1 knockout mice; cell viability, Bax translocation, mitochondrial membrane potential, caspase activity, and Ca2+ release assays; in vivo stroke and tunicamycin models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal readouts, in vivo validation, replicated across cell types and in vivo models\",\n      \"pmids\": [\"15304216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BI-1 reduces resting ER Ca2+ ([Ca2+]er) by increasing Ca2+ leakage from the ER, opposing the action of SERCA; BI-1 functions downstream of Bcl-XL in regulating ER Ca2+ homeostasis, and this regulation is independent of Bax/Bak.\",\n      \"method\": \"ER-targeted cameleon Ca2+ indicator; SERCA co-expression rescue; bi-1-deficient MEFs; bax/bak double-KO cells; Bcl-XL co-expression experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — live-cell Ca2+ imaging with genetic rescue and epistasis experiments using multiple KO backgrounds in one rigorous study\",\n      \"pmids\": [\"18299329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BI-1 promotes autophagy by reducing steady-state ER Ca2+ levels via IP3Rs, thereby lowering mitochondrial Ca2+ uptake, reducing oxygen consumption and ATP levels, and stimulating autophagy; this function is separable from BI-1's modulation of IRE1 signaling.\",\n      \"method\": \"BI-1 overexpression and knockdown; bi-1-/- mice (basal autophagy); IP3R epistasis; oxygen consumption and ATP measurements; tumor xenograft growth\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mice, multiple orthogonal assays (Ca2+, bioenergetics, autophagy flux, xenograft), IP3R epistasis in single study\",\n      \"pmids\": [\"22588718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BAR (bifunctional apoptosis regulator) is an ER-resident RING-type E3 ubiquitin ligase that interacts with BI-1 and promotes its proteasomal degradation; BAR knockdown stabilizes BI-1 protein and enhances inhibition of IRE1 signaling during ER stress; endogenous BAR levels decline under prolonged ER stress.\",\n      \"method\": \"Co-IP; RING-domain mutant BAR; siRNA knockdown; proteasome inhibitor; IRE1 activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction, dominant-negative RING mutant, and functional IRE1 readout in a single focused study\",\n      \"pmids\": [\"21068390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BI-1 has a six-transmembrane topology (not seven) with a putative re-entrant loop at the C-terminus and both N- and C-termini in the cytosol; mutation of charged C-terminal residues of hGAAP (a TMBIM family member used as topology model) abolishes anti-apoptotic function.\",\n      \"method\": \"Topology mapping by selective permeabilization and epitope-tag accessibility; mutagenesis of charged C-terminal residues; functional anti-apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic topology mapping with orthogonal permeabilization methods and mutagenesis-function link in a single study\",\n      \"pmids\": [\"22418439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMBIM6 physically associates with mTORC2 and promotes mTORC2 assembly and activation; ER Ca2+ leak from TMBIM6 affects mTORC2 association with ribosomes. The compound BIA prevents TMBIM6 binding to mTORC2 and inhibits mTORC2 activity and tumor growth.\",\n      \"method\": \"Co-IP of TMBIM6 with mTORC2 components; TMBIM6 KO/KD; BIA antagonist treatment; Ca2+ measurements; glycolysis and lipid synthesis assays; cancer xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, genetic KO, pharmacological inhibitor, multiple downstream pathway readouts, and in vivo xenograft validation in one study\",\n      \"pmids\": [\"32782388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMBIM6-derived ER Ca2+ efflux elevates lysosomal Ca2+ levels independently of IP3Rs; under nutrient starvation or mTOR inhibition, TMBIM6 promotes local Ca2+ release through lysosomal MCOLN1/TRPML1 channels, activating PPP3/calcineurin and TFEB nuclear translocation to induce autophagy and lysosome biogenesis.\",\n      \"method\": \"CEPIA Ca2+ indicators in ER and lysosomes; TMBIM6 KO MEFs and tmbim6-/- mice; MCOLN1 pharmacology (ML-SA1); calcineurin inhibitor; TFEB nuclear translocation imaging; autophagy flux in vivo\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — organelle-specific Ca2+ sensors, genetic KO in cells and mice, pharmacological dissection of MCOLN1 and calcineurin, multiple orthogonal readouts\",\n      \"pmids\": [\"32167007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMBIM6 interacts with VDAC1 and prevents its oligomerization, thereby restraining mitochondrial Ca2+ uptake and maintaining mitochondrial quality control; TMBIM6CKO exacerbates LPS-induced septic cardiomyopathy while TMBIM6TG is protective.\",\n      \"method\": \"Co-IP; mutant TMBIM6 plasmid transfection; molecular docking; TMBIM6CKO and TMBIM6TG mice; LPS sepsis model; mitochondrial respiration, fission, mitophagy, and Ca2+ assays\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, molecular docking, and in vivo genetic models with multiple functional readouts in one study\",\n      \"pmids\": [\"36603706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DNA-PKcs physically interacts with BI-1 and promotes its degradation (post-transcriptionally, without affecting BI-1 transcription); DNA-PKcs knockout stabilizes BI-1, protecting mitochondria from IR injury; double knockout of DNA-PKcs and BI-1 abolishes cardioprotection, placing BI-1 downstream of DNA-PKcs.\",\n      \"method\": \"DNA-PKcsCKO mice; double KO (DNA-PKcs + BI-1); Co-IP; phosphorylation assays; cardiac IR model; mitochondrial fission, mPTP, mitophagy, and Bax-mediated apoptosis assays\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct Co-IP, genetic epistasis via double KO, in vivo cardiac IR model, multiple orthogonal mitochondrial readouts\",\n      \"pmids\": [\"31919590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BI-1 provides endogenous cytoprotection of liver and kidney from ER stress and ischemia-reperfusion injury; bi-1-/- mice show increased histological injury, hepatocyte death, caspase activity, and elevated IRE1, ATF6, CHOP, and spliced XBP-1 after hepatic or renal IR, and bi-1 mRNA is induced by IR in wild-type liver.\",\n      \"method\": \"bi-1 knockout mice; hepatic and renal artery occlusion IR models; TUNEL, caspase assays, serum transaminases, immunoblot for UPR markers\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in two organ systems with multiple orthogonal readouts and in vivo disease model, independent replication of ER stress protection concept\",\n      \"pmids\": [\"16478805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BI-1 modulates the unfolded protein response: it directly interacts with IRE1 and inhibits IRE1 endonuclease activity; BI-1 transgenic neurons and mice show reduced UPR marker induction (CHOP) and reduced brain lesion volume after stroke and traumatic brain injury.\",\n      \"method\": \"BI-1 transgenic mice with neuron-specific promoter; MCAO stroke and controlled cortical impact TBI models; UPR marker immunoblot; primary cortical neuron ER stress assays\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic OE with in vivo disease models and UPR marker readouts; IRE1 interaction inferred from prior published Co-IP (not re-demonstrated here), single lab\",\n      \"pmids\": [\"21075086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BI-1 overexpression protects against neonatal hypoxic-ischemic brain injury by inhibiting the IRE1α branch of the UPR and in part the PERK branch; silencing BI-1 or activating IRE1α with a CRISPR activation plasmid reverses protection.\",\n      \"method\": \"Adenoviral TMBIM6 overexpression in vivo (rat pup HI model) and in vitro (OGD); CRISPR activation of IRE1α; siRNA silencing; infarct area, neurodegeneration, and long-term behavioral outcomes\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — viral OE plus epistasis via CRISPR/siRNA, in vivo and in vitro confirmation, single lab\",\n      \"pmids\": [\"31636086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BI-1 disrupts the NPR-CYP2E1 complex and upregulates Nrf-2/HO-1, reducing ER stress-induced ROS production; silencing either BI-1 or Nrf-2 reverses protection after neonatal HI injury.\",\n      \"method\": \"Adenoviral TMBIM6 overexpression; siRNA silencing of BI-1 and Nrf-2; NPR-CYP2E1 complex analysis by Co-IP; DHE ROS staining; HO-1 activity; in vivo rat HI model\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for NPR-CYP complex, siRNA epistasis, in vivo model; single lab, mechanistic chain partially inferred\",\n      \"pmids\": [\"31472686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BI-1 protects against obesity-induced hepatic insulin resistance by reducing CYP2E1 activity and CYP2E1-dependent ROS production; BI-1 KO mice fed a high-fat diet showed increased CYP2E1 activity and ER stress, while stable BI-1 expression in HepG2 cells reduced palmitate-induced ER stress and CYP2E1-dependent ROS, preserving insulin signaling.\",\n      \"method\": \"bi-1 KO mice on high-fat diet; stable TMBIM6 expression in HepG2; CYP2E1 activity assay; ROS measurement; glucose/insulin tolerance tests; ER stress markers by immunoblot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and stable OE with enzyme activity assay and functional metabolic readouts; single lab\",\n      \"pmids\": [\"27576594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Klf10 transcription factor directly binds the BI-1 promoter and suppresses BI-1 transcription; estrogen-induced Klf10 reduces BI-1 expression, causing cytosolic Ca2+ increase and apoptosis in breast cancer cells. Mutation of the Klf10 binding element in the BI-1 promoter reverses estrogen-induced repression.\",\n      \"method\": \"ChIP-chip; BI-1 promoter reporter assays; EMSA; siRNA-Klf10; Ca2+ imaging; apoptosis assays\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, EMSA, promoter mutagenesis, and functional Ca2+/apoptosis readouts; single lab\",\n      \"pmids\": [\"21262377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sp1 is the essential transcription factor for basal TMBIM6 promoter activity (core promoter -133/+30 bp); PKC activation (via PKCι, PKCε, PKCδ) enhances TMBIM6 expression by promoting nuclear translocation of Sp1.\",\n      \"method\": \"Reporter gene assays with promoter deletions and mutations; EMSA; supershift assay; ChIP; siRNA against Sp1; mithramycin-A inhibition; PKC active-mutant overexpression; nuclear fractionation\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal promoter assays (EMSA, ChIP, reporter mutations, supershift), single lab\",\n      \"pmids\": [\"31336725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM15-mediated m6A modification of TMBIM6 mRNA enhances TMBIM6 mRNA stability in an IGF2BP3-dependent manner in laryngeal squamous cell carcinoma.\",\n      \"method\": \"m6A microarray; MeRIP-seq; RIP assay; RNase MazF methylation site mapping; actinomycin D mRNA stability assay; RBM15 knockdown/overexpression\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq, RIP, RNase MazF site mapping, and mRNA stability assay; single lab\",\n      \"pmids\": [\"33637103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMBIM6 deficiency leads to redox-mediated posttranslational modifications of IRE1α (S-nitrosylation and sulfonation); sulfonation of IRE1α enhances RIDD activity causing TMBIM6 mRNA decay (creating a feedback loop), while S-nitrosylation inhibits XBP1 splicing promoting cell death in aging liver.\",\n      \"method\": \"TMBIM6-/- mice and human aging liver samples; S-nitrosylation and sulfonation detection; IRE1α endonuclease (RIDD and XBP1 splicing) activity assays; TMBIM6 rescue in KO old mice and stable hepatic cell lines\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical PTM detection combined with genetic KO/rescue and functional IRE1α activity assays; single lab\",\n      \"pmids\": [\"34562874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human TEGT/TMBIM6 protein localizes primarily to the endoplasmic reticulum; in vitro translation requires microsomes for efficient synthesis, and the protein shows no signal peptide cleavage, N-linked, or O-linked glycosylation; it tends to self-aggregate due to hydrophobicity.\",\n      \"method\": \"Immunofluorescence of HA-tagged hTEGT; in vitro translation with/without microsomes; SDS-PAGE and glycosylation analysis\",\n      \"journal\": \"Molecular membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization experiment with functional implication (ER targeting for translation) and biochemical characterization; single early study\",\n      \"pmids\": [\"10087504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BI-1 deficiency accelerates liver regeneration after partial hepatectomy: bi-1-/- hepatocytes enter the cell cycle faster, with earlier cyclin D1/D3/Cdk2/Cdk4 induction, faster Rb hyperphosphorylation, p27Kip1 degradation, and accelerated calcineurin-dependent NFAT1 nuclear translocation, linking BI-1's ER Ca2+ regulation to cell proliferation control.\",\n      \"method\": \"Partial hepatectomy in bi-1-/- vs wild-type mice; BrdU incorporation; cyclin/Cdk immunoblot; Rb phosphorylation; p27 levels; NFAT1 nuclear translocation; calcineurin substrate dephosphorylation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO model with multiple cell-cycle readouts and Ca2+/calcineurin mechanistic link; single lab\",\n      \"pmids\": [\"17308082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BI-1 overexpression activates ERK1/2, which suppresses mitochondria-derived ROS production; ERK or BI-1 siRNA knockdown reverses the anti-apoptotic and anti-ROS effects, placing ERK1/2 activation downstream of BI-1 in stress protection.\",\n      \"method\": \"BI-1 overexpression in cells; ERK siRNA knockdown; BI-1 siRNA; ROS measurement; apoptosis assays; MEFs from BI-1 transgenic mice\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA epistasis with ROS and apoptosis functional readouts, confirmed in transgenic MEFs; single lab\",\n      \"pmids\": [\"22309999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TMBIM6 enhances autophagy and protects against CsA-induced nephrotoxicity by activating lysosomal function; TMBIM6-expressing cells maintain AMPK phosphorylation, suppress mTORC1, and upregulate TFEB (lysosome biogenesis factor); tmbim6-/- mice show impaired autophagic clearance and increased CsA kidney injury.\",\n      \"method\": \"TMBIM6-expressing HK-2 cells; tmbim6-/- mice; CsA treatment; autophagosome and lysosome markers; AMPK/mTORC1/TFEB immunoblot; lysosomal activity assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mice and stable OE cells with multiple signaling and functional readouts; single lab\",\n      \"pmids\": [\"26305401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMBIM6 protects against cisplatin-induced testicular toxicity by inducing HO-1 (via Akt-Nrf2 axis) and enhancing ER folding capacity, reducing PDI carbonylation and oxidative stress; TMBIM6 KO mice show loss of protection, rescued by lentiviral TMBIM6 re-expression in testis.\",\n      \"method\": \"Tmbim6 KO and Tmbim6-overexpressing TM3 Leydig cells; lentiviral testicular rescue; HO-1 activity and Nrf2 immunoblot; PDI carbonylation; ROS; testosterone synthesis enzyme levels\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with lentiviral rescue, multiple biochemical readouts; single lab\",\n      \"pmids\": [\"29309588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BI-1 overexpression leads to extracellular acidification via altered mitochondrial metabolism, promoting monocarboxylate transporter (MCT) upregulation downstream of NHE activation; MCT inhibition with lonidamine blocks extracellular acidification and suppresses cancer cell migration, invasion, and MMP2/9 activity in BI-1-overexpressing cells.\",\n      \"method\": \"pH measurement; NHE and MCT inhibitors; siRNA; MMP activity assays; migration/invasion assays in BI-1-overexpressing HT1080 cells\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological inhibitors only, mechanistic chain largely inferred from inhibitor effects\",\n      \"pmids\": [\"21537843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BI-1 overexpression sensitizes cells to Fas-induced death through a mechanism involving intracellular pH drop, BI-1 oligomerization, mitochondrial Ca2+ accumulation, and significant inhibition of sodium-hydrogen exchanger (NHE) activity.\",\n      \"method\": \"BI-1-overexpressing HT1080 cells; Fas treatment; cytosolic pH measurement; NHE inhibitor (EIPA) and siRNA; Ca2+ accumulation assay; caspase-3 assay\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological and siRNA approach, mechanistic details partially inferred\",\n      \"pmids\": [\"24314142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMBIM6 regulates mitochondrial Ca2+ homeostasis and mitochondrial quality surveillance (MQS) through a TMBIM6-VDAC1 interaction; hypoxia-induced TMBIM6 blockade over-activates VDAC1 (major mitochondrial Ca2+ uptake route), causing Ca2+ overload; ZSHX decoction increases TMBIM6 expression, inhibits VDAC1-mediated Ca2+ overload, and normalizes MQS.\",\n      \"method\": \"TMBIM6CKO, TMBIM6TG, and VDAC1TG mice; ischemic myocardial injury model; Ca2+ and mitochondrial function assays\",\n      \"journal\": \"Phytomedicine : international journal of phytotherapy and phytopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic mouse models with functional readouts, but mechanistic TMBIM6-VDAC1 interaction evidence here is indirect (supported more directly by PMID 36603706)\",\n      \"pmids\": [\"38870748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMBIM6 serves as a negative regulator of osteoclastogenesis by scavenging ROS and preventing NF-κB p65 nuclear localization; Tmbim6-KO mice show an osteoporotic phenotype; TMBIM6 controls redox regulation via NRF2 signaling.\",\n      \"method\": \"Tmbim6-KO mice; osteoclast differentiation assays; TRAP staining; ROS scavenging assays; p65 nuclear localization; N-acetylcysteine rescue; transcriptome analysis; NRF2 pathway immunoblot\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo and in vitro with multiple mechanistic readouts including epistasis via antioxidant rescue; single lab\",\n      \"pmids\": [\"37399733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMBIM6 agonism in cancer cells activates cytosolic Ca2+ and ROS, induces lysosome biogenesis, and triggers paraptosis via ERAD II mechanisms; this occurs independent of canonical p38 MAPK, JNK, ERK, UPR, autophagy, proteasomes, or Caspase-9 pathways; TMBIM6 undergoes conformational changes upon intracellular environment (ICE) change that dictate its function.\",\n      \"method\": \"TMBIM6 agonist treatment; pathway inhibitors; Ca2+ and ROS measurements; lysosome biogenesis assays; xenograft models; paraptosis morphological analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological agonism with multiple pathway inhibitors, Ca2+/ROS readouts, and in vivo xenograft; single lab, mechanistic chain partially by exclusion\",\n      \"pmids\": [\"39609612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TMBIM6 directly binds IRE1α and inhibits its activation in dopaminergic neurons; α-synuclein preformed fibrils disrupt the TMBIM6-IRE1α complex; pharmacological or genetic IRE1α inhibition prevents cell death in TMBIM6-deficient cells; AAV-mediated TMBIM6 overexpression in mice improves motor function and dopaminergic neuron survival in Parkinson's disease models.\",\n      \"method\": \"Co-IP of TMBIM6-IRE1α; TMBIM6 KD/OE in DAergic cells and primary neurons; aSyn PFF treatment; IRE1α inhibitor rescue; Drosophila rotenone model; AAV mouse overexpression; single-cell RNA-seq\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, pharmacological epistasis, multiple in vivo models (Drosophila and mouse AAV); single lab, published 2026\",\n      \"pmids\": [\"41932887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CSDE1 (an RNA-binding protein) competes with AGO2 for binding to TMBIM6 mRNA, protecting it from miR-20a-5p-mediated silencing and enhancing TMBIM6 protein levels post-transcriptionally without affecting mRNA abundance; an RNA-binding mutant of CSDE1 fails to compete with AGO2.\",\n      \"method\": \"RIP of CSDE1 and AGO2 on TMBIM6 mRNA; RNA-binding mutant CSDE1; miR-20a-5p overexpression; TMBIM6 protein and mRNA measurement\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP demonstrating competitive binding, mutagenesis of CSDE1 RNA-binding domain, functional protein readout; single lab\",\n      \"pmids\": [\"41093770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3-mediated m6A modification of TMBIM6 mRNA, read by YTHDF2, decreases TMBIM6 mRNA stability and expression in preeclamptic trophoblasts; YTHDF2 knockdown increases TMBIM6 mRNA stability; TMBIM6 overexpression counteracts METTL3-driven ER stress and trophoblast dysfunction.\",\n      \"method\": \"MeRIP-qPCR; shRNA knockdown of METTL3 and YTHDF2; mRNA stability assay; TMBIM6 overexpression rescue; ER stress and apoptosis assays in HTR-8/SVneo cells; preeclamptic rat model\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP and mRNA stability assay plus genetic rescue; single lab\",\n      \"pmids\": [\"36747144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TCF3 transcription factor directly binds the TMBIM6 promoter and transcriptionally activates TMBIM6 expression; TMBIM6 overexpression reduces intracellular Ca2+ and promotes ferroptosis resistance in bladder cancer, while TMBIM6 knockdown reverses TCF3-mediated effects.\",\n      \"method\": \"ChIP and luciferase assays for TCF3/TMBIM6 promoter interaction; TMBIM6 OE and KD; BAPTA-AM Ca2+ chelation; ferroptosis markers (GPX4, SLC7A11, MDA, Fe2+, lipid ROS); Erastin treatment; xenograft model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase for direct transcriptional activation, Ca2+ chelation epistasis, in vivo xenograft; single lab\",\n      \"pmids\": [\"40610429\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMBIM6/BI-1 is an evolutionarily conserved, six-transmembrane ER-resident protein that functions as a Ca2+ leak channel, reducing resting ER [Ca2+] and thereby regulating downstream Ca2+-dependent processes including: inhibition of Bax activation and ER stress-induced apoptosis (acting downstream of Bcl-XL and upstream of mitochondrial apoptosis), direct inhibition of IRE1α endonuclease activity to modulate UPR signaling, promotion of autophagy via IP3R-dependent lowering of mitochondrial bioenergetics and via lysosomal MCOLN1/calcineurin/TFEB activation, interaction with and prevention of VDAC1 oligomerization to maintain mitochondrial Ca2+ homeostasis, assembly with mTORC2 to promote its activation and downstream AKT/metabolic signaling in cancer, and transcriptional regulation by Sp1/PKC and post-translational regulation by the E3 ligase BAR; its expression is also post-transcriptionally controlled by m6A modification (written by RBM15/METTL3, read by IGF2BP3/YTHDF2) and by competition between CSDE1 and AGO2/miRNAs for TMBIM6 mRNA.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMBIM6 (BI-1/TEGT) is an endoplasmic reticulum-resident, six-transmembrane protein that governs cell fate under stress by acting as a Ca2+ leak channel that lowers resting ER Ca2+, thereby tuning a broad network of Ca2+-dependent survival, autophagy, and metabolic responses [#0, #1, #4, #18]. Its loss selectively sensitizes cells to ER stress-induced apoptosis by permitting Bax activation and mitochondrial damage, an anti-apoptotic activity that operates downstream of Bcl-XL and independently of Bax/Bak in setting ER Ca2+ tone [#0, #1]. A central effector arm is the unfolded protein response: TMBIM6 directly binds IRE1\\u03b1 and restrains its endonuclease activity, limiting UPR marker induction and protecting neurons and liver in stroke, hypoxic-ischemic, and aging models [#10, #11, #28]; under TMBIM6 deficiency, redox-driven modifications of IRE1\\u03b1 (S-nitrosylation and sulfonation) further dysregulate XBP1 splicing and RIDD, the latter degrading TMBIM6 mRNA in a feedback loop [#17]. TMBIM6-derived ER Ca2+ efflux also drives autophagy through two routes: an IP3R-dependent lowering of mitochondrial Ca2+ uptake and bioenergetics, and an IP3R-independent elevation of lysosomal Ca2+ via MCOLN1 that activates calcineurin and TFEB to promote lysosome biogenesis [#2, #6, #21]. At the mitochondrial interface, TMBIM6 binds VDAC1 and prevents its oligomerization to restrain mitochondrial Ca2+ overload and preserve mitochondrial quality control [#7]. Beyond stress protection, TMBIM6 associates with mTORC2 to promote its assembly and downstream metabolic signaling in cancer [#5], and limits oxidative stress through Nrf2/HO-1 and CYP2E1-directed mechanisms across hepatic, testicular, and bone contexts [#13, #22, #26]. TMBIM6 abundance is controlled at multiple levels: transcriptionally by Sp1/PKC, Klf10, TCF3, and TGF-responsive inputs [#14, #15, #31], post-transcriptionally by opposing m6A readers and by CSDE1/AGO2 competition for its mRNA [#16, #29, #30], and post-translationally by E3 ligase BAR and by DNA-PKcs-promoted degradation [#3, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established TMBIM6/BI-1 as an ER-localized, selective inhibitor of ER stress-induced apoptosis, defining the core question of how an ER protein blocks the mitochondrial death step.\",\n      \"evidence\": \"bi-1 knockout mice with Bax translocation, mitochondrial potential, caspase, and ER Ca2+ readouts plus in vivo stroke/tunicamycin models\",\n      \"pmids\": [\"15304216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the channel mechanism linking BI-1 to reduced ER Ca2+\", \"Direct molecular partners not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed endogenous BI-1 protects organs from ischemia-reperfusion injury, extending the apoptosis findings to in vivo physiological stress and linking loss to UPR marker elevation.\",\n      \"evidence\": \"bi-1 knockout mice in hepatic and renal IR with UPR marker immunoblot and injury readouts\",\n      \"pmids\": [\"16478805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting BI-1 to specific UPR branches not resolved here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the biochemical basis of protection: BI-1 lowers resting ER Ca2+ by promoting Ca2+ leak downstream of Bcl-XL and independently of Bax/Bak.\",\n      \"evidence\": \"ER-targeted cameleon imaging with SERCA rescue and epistasis in multiple KO backgrounds\",\n      \"pmids\": [\"18299329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of channel pore activity by reconstitution not shown\", \"Structural basis of Ca2+ conduction unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified two distinct regulatory nodes: direct inhibition of IRE1 endonuclease activity (UPR control) and BAR-mediated proteasomal degradation (protein turnover control).\",\n      \"evidence\": \"BI-1 transgenic mice in stroke/TBI for IRE1/UPR readouts; Co-IP, RING-mutant, and proteasome inhibition for BAR\",\n      \"pmids\": [\"21075086\", \"21068390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IRE1 interaction in the transgenic study inferred from prior Co-IP, not re-demonstrated\", \"Whether BAR degradation is stress-regulated in vivo not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected ER Ca2+ regulation to downstream physiology, showing BI-1 promotes autophagy via IP3R-dependent lowering of mitochondrial bioenergetics, and activates ERK1/2 to suppress ROS.\",\n      \"evidence\": \"bi-1-/- mice and overexpression with IP3R epistasis, bioenergetics, autophagy flux, xenografts; ERK siRNA epistasis with ROS/apoptosis readouts\",\n      \"pmids\": [\"22588718\", \"22309999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Autophagy and IRE1 functions stated to be separable but molecular branch point undefined\", \"ERK activation mechanism downstream of BI-1 not detailed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the membrane topology as six transmembrane domains with cytosolic termini, providing the structural framework for the Ca2+ leak and anti-apoptotic activity.\",\n      \"evidence\": \"Topology mapping by selective permeabilization and epitope accessibility with charged-residue mutagenesis\",\n      \"pmids\": [\"22418439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the channel not determined\", \"Topology partly modeled via TMBIM family member hGAAP\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped transcriptional control of TMBIM6, establishing Sp1/PKC as basal activators and Klf10 and CYP2E1/Nrf2 axes as context-specific modulators of expression and redox protection.\",\n      \"evidence\": \"Promoter reporter, EMSA, ChIP, supershift for Sp1; adenoviral OE and siRNA epistasis in HI and metabolic models for CYP2E1/Nrf2\",\n      \"pmids\": [\"31336725\", \"31472686\", \"31636086\", \"27576594\", \"21262377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration of multiple transcription factors in a single cell type untested\", \"Redox mechanistic chains partly inferred from inhibitor/siRNA effects\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the interactome beyond apoptosis, showing TMBIM6 binds mTORC2 to promote its assembly and activation, and drives lysosomal autophagy via an IP3R-independent MCOLN1/calcineurin/TFEB route.\",\n      \"evidence\": \"Reciprocal Co-IP, KO/KD, BIA antagonist, xenografts for mTORC2; organelle-specific Ca2+ sensors, KO mice, and MCOLN1/calcineurin pharmacology for the lysosomal axis\",\n      \"pmids\": [\"32782388\", \"32167007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TMBIM6-mTORC2 association undefined\", \"How ER Ca2+ leak is locally directed to lysosomes vs mitochondria unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified DNA-PKcs as a post-transcriptional negative regulator that promotes BI-1 degradation, placing BI-1 downstream of DNA-PKcs in mitochondrial cardioprotection.\",\n      \"evidence\": \"DNA-PKcs CKO and DNA-PKcs/BI-1 double KO mice with Co-IP and cardiac IR mitochondrial readouts\",\n      \"pmids\": [\"31919590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DNA-PKcs phosphorylates BI-1 directly to trigger degradation not pinned down\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed reciprocal regulation between TMBIM6 and IRE1\\u03b1 redox state, with TMBIM6 loss enabling IRE1\\u03b1 sulfonation/S-nitrosylation that feeds back to degrade TMBIM6 mRNA, and defined m6A control of TMBIM6 abundance.\",\n      \"evidence\": \"TMBIM6-/- mice and aging liver with PTM detection and IRE1\\u03b1 activity assays; MeRIP-seq, RIP, and mRNA stability for RBM15/IGF2BP3\",\n      \"pmids\": [\"34562874\", \"33637103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct causal ordering of IRE1\\u03b1 PTMs versus TMBIM6 loss not fully separated\", \"m6A control demonstrated in a single cancer context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established the TMBIM6-VDAC1 interaction as the mechanism preventing mitochondrial Ca2+ overload, linking TMBIM6 to mitochondrial quality control in cardiac disease.\",\n      \"evidence\": \"Co-IP, mutagenesis, molecular docking, and CKO/TG mouse models in septic and ischemic cardiomyopathy\",\n      \"pmids\": [\"36603706\", \"38870748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface of the TMBIM6-VDAC1 contact not solved\", \"ZSHX decoction effect on the interaction is indirect\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that pharmacological TMBIM6 agonism flips its survival role to a death-promoting one, inducing Ca2+/ROS-driven paraptosis via ERAD II, indicating conformation-dependent functional switching.\",\n      \"evidence\": \"TMBIM6 agonist with pathway inhibitor panel, Ca2+/ROS and lysosome readouts, paraptosis morphology, and xenografts\",\n      \"pmids\": [\"39609612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conformational change model inferred, not directly visualized\", \"Death mechanism defined largely by exclusion of canonical pathways\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended regulatory control to competitive RNA-binding and disease-specific transcriptional activation, defining CSDE1/AGO2 competition and TCF3/m6A inputs that set TMBIM6 levels and influence ferroptosis resistance.\",\n      \"evidence\": \"RIP and CSDE1 RNA-binding mutant for AGO2 competition; ChIP/luciferase for TCF3; MeRIP and YTHDF2 knockdown for m6A; ferroptosis and Ca2+ chelation readouts\",\n      \"pmids\": [\"41093770\", \"40610429\", \"36747144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these regulatory layers co-occur in the same cell type untested\", \"Single-lab findings per regulatory mechanism\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a neuroprotective TMBIM6-IRE1\\u03b1 axis in dopaminergic neurons, with \\u03b1-synuclein fibrils disrupting the complex, connecting TMBIM6's UPR control to Parkinson's disease models.\",\n      \"evidence\": \"Co-IP, KD/OE in DAergic cells, IRE1\\u03b1 inhibitor rescue, Drosophila and AAV mouse PD models, single-cell RNA-seq\",\n      \"pmids\": [\"41932887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How \\u03b1Syn fibrils mechanistically disrupt the complex undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMBIM6 conducts Ca2+ at atomic resolution and how a single ER channel coordinately partitions its ER-mitochondria-lysosome Ca2+ output to select among apoptosis, autophagy, and metabolic outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution channel structure\", \"Mechanism that routes Ca2+ leak to specific downstream effectors unknown\", \"Determinants of the survival-versus-death functional switch unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 5, 7, 28]},\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [13, 22, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 18, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 10, 17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 27]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 6, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"mTORC2\"],\n    \"partners\": [\"IRE1\\u03b1\", \"VDAC1\", \"BAR\", \"DNA-PKcs\", \"Bcl-XL\", \"mTORC2\", \"CSDE1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}