Affinage

TMBIM6

Bax inhibitor 1 · UniProt P55061

Length
237 aa
Mass
26.5 kDa
Annotated
2026-06-10
92 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2004 High

    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

    PMID:15304216

    Open questions at the time
    • Did not define the channel mechanism linking BI-1 to reduced ER Ca2+
    • Direct molecular partners not identified
  2. 2006 High

    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

    PMID:16478805

    Open questions at the time
    • Mechanism connecting BI-1 to specific UPR branches not resolved here
  3. 2008 High

    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

    PMID:18299329

    Open questions at the time
    • Direct demonstration of channel pore activity by reconstitution not shown
    • Structural basis of Ca2+ conduction unresolved
  4. 2010 Medium

    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

    PMID:21068390 PMID:21075086

    Open questions at the time
    • IRE1 interaction in the transgenic study inferred from prior Co-IP, not re-demonstrated
    • Whether BAR degradation is stress-regulated in vivo not established
  5. 2012 High

    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

    PMID:22309999 PMID:22588718

    Open questions at the time
    • Autophagy and IRE1 functions stated to be separable but molecular branch point undefined
    • ERK activation mechanism downstream of BI-1 not detailed
  6. 2012 High

    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

    PMID:22418439

    Open questions at the time
    • High-resolution structure of the channel not determined
    • Topology partly modeled via TMBIM family member hGAAP
  7. 2019 Medium

    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

    PMID:21262377 PMID:27576594 PMID:31336725 PMID:31472686 PMID:31636086

    Open questions at the time
    • Integration of multiple transcription factors in a single cell type untested
    • Redox mechanistic chains partly inferred from inhibitor/siRNA effects
  8. 2020 High

    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

    PMID:32167007 PMID:32782388

    Open questions at the time
    • Structural basis of TMBIM6-mTORC2 association undefined
    • How ER Ca2+ leak is locally directed to lysosomes vs mitochondria unresolved
  9. 2020 High

    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

    PMID:31919590

    Open questions at the time
    • Whether DNA-PKcs phosphorylates BI-1 directly to trigger degradation not pinned down
  10. 2021 Medium

    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

    PMID:33637103 PMID:34562874

    Open questions at the time
    • Direct causal ordering of IRE1α PTMs versus TMBIM6 loss not fully separated
    • m6A control demonstrated in a single cancer context
  11. 2023 High

    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

    PMID:36603706 PMID:38870748

    Open questions at the time
    • Structural interface of the TMBIM6-VDAC1 contact not solved
    • ZSHX decoction effect on the interaction is indirect
  12. 2024 Medium

    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

    PMID:39609612

    Open questions at the time
    • Conformational change model inferred, not directly visualized
    • Death mechanism defined largely by exclusion of canonical pathways
  13. 2025 Medium

    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

    PMID:36747144 PMID:40610429 PMID:41093770

    Open questions at the time
    • Whether these regulatory layers co-occur in the same cell type untested
    • Single-lab findings per regulatory mechanism
  14. 2026 Medium

    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

    PMID:41932887

    Open questions at the time
    • How αSyn fibrils mechanistically disrupt the complex undefined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0005215 transporter activity 3 GO:0016209 antioxidant activity 3
Localization
GO:0005783 endoplasmic reticulum 4
Pathway
R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 3 R-HSA-162582 Signal Transduction 1
Partners
BARBCL-XLCSDE1DNA-PKCSIRE1ΑMTORC2VDAC1
Complex memberships
mTORC2

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 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+. bi-1 knockout mice; cell viability, Bax translocation, mitochondrial membrane potential, caspase activity, and Ca2+ release assays; in vivo stroke and tunicamycin models Molecular cell High 15304216
2008 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. ER-targeted cameleon Ca2+ indicator; SERCA co-expression rescue; bi-1-deficient MEFs; bax/bak double-KO cells; Bcl-XL co-expression experiments The Journal of biological chemistry High 18299329
2012 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. BI-1 overexpression and knockdown; bi-1-/- mice (basal autophagy); IP3R epistasis; oxygen consumption and ATP measurements; tumor xenograft growth Genes & development High 22588718
2010 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. Co-IP; RING-domain mutant BAR; siRNA knockdown; proteasome inhibitor; IRE1 activity assays The Journal of biological chemistry High 21068390
2012 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. Topology mapping by selective permeabilization and epitope-tag accessibility; mutagenesis of charged C-terminal residues; functional anti-apoptosis assays The Journal of biological chemistry High 22418439
2020 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. Co-IP of TMBIM6 with mTORC2 components; TMBIM6 KO/KD; BIA antagonist treatment; Ca2+ measurements; glycolysis and lipid synthesis assays; cancer xenograft models Nature communications High 32782388
2020 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. 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 Autophagy High 32167007
2023 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. Co-IP; mutant TMBIM6 plasmid transfection; molecular docking; TMBIM6CKO and TMBIM6TG mice; LPS sepsis model; mitochondrial respiration, fission, mitophagy, and Ca2+ assays Metabolism: clinical and experimental High 36603706
2020 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. 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 Basic research in cardiology High 31919590
2006 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. bi-1 knockout mice; hepatic and renal artery occlusion IR models; TUNEL, caspase assays, serum transaminases, immunoblot for UPR markers Proceedings of the National Academy of Sciences of the United States of America High 16478805
2010 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. 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 Brain research Medium 21075086
2019 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. 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 Disease models & mechanisms Medium 31636086
2019 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. 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 of neuroinflammation Medium 31472686
2016 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. 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 Scientific reports Medium 27576594
2011 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. ChIP-chip; BI-1 promoter reporter assays; EMSA; siRNA-Klf10; Ca2+ imaging; apoptosis assays The international journal of biochemistry & cell biology Medium 21262377
2019 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. Reporter gene assays with promoter deletions and mutations; EMSA; supershift assay; ChIP; siRNA against Sp1; mithramycin-A inhibition; PKC active-mutant overexpression; nuclear fractionation Cancers Medium 31336725
2021 RBM15-mediated m6A modification of TMBIM6 mRNA enhances TMBIM6 mRNA stability in an IGF2BP3-dependent manner in laryngeal squamous cell carcinoma. m6A microarray; MeRIP-seq; RIP assay; RNase MazF methylation site mapping; actinomycin D mRNA stability assay; RBM15 knockdown/overexpression Journal of experimental & clinical cancer research : CR Medium 33637103
2021 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. 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 Redox biology Medium 34562874
1998 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. Immunofluorescence of HA-tagged hTEGT; in vitro translation with/without microsomes; SDS-PAGE and glycosylation analysis Molecular membrane biology Medium 10087504
2007 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. Partial hepatectomy in bi-1-/- vs wild-type mice; BrdU incorporation; cyclin/Cdk immunoblot; Rb phosphorylation; p27 levels; NFAT1 nuclear translocation; calcineurin substrate dephosphorylation Cancer research Medium 17308082
2012 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. BI-1 overexpression in cells; ERK siRNA knockdown; BI-1 siRNA; ROS measurement; apoptosis assays; MEFs from BI-1 transgenic mice Biochimica et biophysica acta Medium 22309999
2015 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. TMBIM6-expressing HK-2 cells; tmbim6-/- mice; CsA treatment; autophagosome and lysosome markers; AMPK/mTORC1/TFEB immunoblot; lysosomal activity assays Autophagy Medium 26305401
2018 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. Tmbim6 KO and Tmbim6-overexpressing TM3 Leydig cells; lentiviral testicular rescue; HO-1 activity and Nrf2 immunoblot; PDI carbonylation; ROS; testosterone synthesis enzyme levels Human reproduction (Oxford, England) Medium 29309588
2011 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. pH measurement; NHE and MCT inhibitors; siRNA; MMP activity assays; migration/invasion assays in BI-1-overexpressing HT1080 cells International journal of oncology Low 21537843
2014 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. BI-1-overexpressing HT1080 cells; Fas treatment; cytosolic pH measurement; NHE inhibitor (EIPA) and siRNA; Ca2+ accumulation assay; caspase-3 assay BMB reports Low 24314142
2023 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. TMBIM6CKO, TMBIM6TG, and VDAC1TG mice; ischemic myocardial injury model; Ca2+ and mitochondrial function assays Phytomedicine : international journal of phytotherapy and phytopharmacology Low 38870748
2023 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. Tmbim6-KO mice; osteoclast differentiation assays; TRAP staining; ROS scavenging assays; p65 nuclear localization; N-acetylcysteine rescue; transcriptome analysis; NRF2 pathway immunoblot Redox biology Medium 37399733
2024 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. TMBIM6 agonist treatment; pathway inhibitors; Ca2+ and ROS measurements; lysosome biogenesis assays; xenograft models; paraptosis morphological analysis Oncogene Medium 39609612
2026 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. 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 Cell death & disease Medium 41932887
2025 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. RIP of CSDE1 and AGO2 on TMBIM6 mRNA; RNA-binding mutant CSDE1; miR-20a-5p overexpression; TMBIM6 protein and mRNA measurement RNA (New York, N.Y.) Medium 41093770
2022 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. 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 Molecular medicine (Cambridge, Mass.) Medium 36747144
2025 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. 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 Cell death discovery Medium 40610429

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Molecular cell 242 15304216
2021 RBM15 facilitates laryngeal squamous cell carcinoma progression by regulating TMBIM6 stability through IGF2BP3 dependent. Journal of experimental & clinical cancer research : CR 207 33637103
2006 Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury. Proceedings of the National Academy of Sciences of the United States of America 146 16478805
2020 DNA-PKcs promotes cardiac ischemia reperfusion injury through mitigating BI-1-governed mitochondrial homeostasis. Basic research in cardiology 130 31919590
1999 Evolutionally conserved plant homologue of the Bax inhibitor-1 (BI-1) gene capable of suppressing Bax-induced cell death in yeast(1). FEBS letters 108 10618494
2021 Quercetin Improves Cardiomyocyte Vulnerability to Hypoxia by Regulating SIRT1/TMBIM6-Related Mitophagy and Endoplasmic Reticulum Stress. Oxidative medicine and cellular longevity 95 33859776
2023 Zishenhuoxue decoction-induced myocardial protection against ischemic injury through TMBIM6-VDAC1-mediated regulation of calcium homeostasis and mitochondrial quality surveillance. Phytomedicine : international journal of phytotherapy and phytopharmacology 88 38870748
2008 BI-1 regulates endoplasmic reticulum Ca2+ homeostasis downstream of Bcl-2 family proteins. The Journal of biological chemistry 87 18299329
2023 TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury. Metabolism: clinical and experimental 85 36603706
2012 Endoplasmic reticulum protein BI-1 regulates Ca²⁺-mediated bioenergetics to promote autophagy. Genes & development 78 22588718
2002 Molecular characterization of two plant BI-1 homologues which suppress Bax-induced apoptosis in human 293 cells. Planta 63 12520328
2008 The Bax Inhibitor-1 (BI-1) family in apoptosis and tumorigenesis. Current molecular medicine 62 18336295
2010 Endoplasmic reticulum protein BI-1 modulates unfolded protein response signaling and protects against stroke and traumatic brain injury. Brain research 59 21075086
2020 TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation. Nature communications 55 32782388
2020 TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy through regulation of lysosomal calcium. Autophagy 52 32167007
2012 Six-transmembrane topology for Golgi anti-apoptotic protein (GAAP) and Bax inhibitor 1 (BI-1) provides model for the transmembrane Bax inhibitor-containing motif (TMBIM) family. The Journal of biological chemistry 43 22418439
2018 Single domain based bispecific antibody, Muc1-Bi-1, and its humanized form, Muc1-Bi-2, induce potent cancer cell killing in muc1 positive tumor cells. PloS one 41 29357376
2011 Klf10 induces cell apoptosis through modulation of BI-1 expression and Ca2+ homeostasis in estrogen-responding adenocarcinoma cells. The international journal of biochemistry & cell biology 36 21262377
2004 Pretargeted alpha emitting radioimmunotherapy using (213)Bi 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-biotin. Clinical cancer research : an official journal of the American Association for Cancer Research 34 15131055
2010 Bifunctional apoptosis regulator (BAR), an endoplasmic reticulum (ER)-associated E3 ubiquitin ligase, modulates BI-1 protein stability and function in ER Stress. The Journal of biological chemistry 32 21068390
1995 Identification of a novel conserved human gene, TEGT. Genomics 32 8530040
2015 TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model. Autophagy 30 26305401
2019 Adenoviral TMBIM6 vector attenuates ER-stress-induced apoptosis in a neonatal hypoxic-ischemic rat model. Disease models & mechanisms 26 31636086
2021 BI-1 ameliorates myocardial injury by activating the mitochondrial unfolded protein response and FUNDC1-related mitophagy in cardiorenal syndrome type 3. Cellular signalling 24 34921980
2012 Role of BI-1 (TEGT)-mediated ERK1/2 activation in mitochondria-mediated apoptosis and splenomegaly in BI-1 transgenic mice. Biochimica et biophysica acta 24 22309999
2023 Methyltransferase-like 3 aggravates endoplasmic reticulum stress in preeclampsia by targeting TMBIM6 in YTHDF2-dependent manner. Molecular medicine (Cambridge, Mass.) 23 36747144
2023 Two-Dimensional Cs2 AgInx Bi1- x Cl6 Alloyed Double Perovskite Nanoplatelets for Solution-Processed Light-Emitting Diodes. Advanced materials (Deerfield Beach, Fla.) 23 36906925
2007 Mice lacking bi-1 gene show accelerated liver regeneration. Cancer research 23 17308082
2023 STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent. Journal of experimental & clinical cancer research : CR 21 36639675
2016 Luminescent osmium(ii) bi-1,2,3-triazol-4-yl complexes: photophysical characterisation and application in light-emitting electrochemical cells. Dalton transactions (Cambridge, England : 2003) 19 27055067
2018 Transmembrane BAX Inhibitor Motif-6 (TMBIM6) protects against cisplatin-induced testicular toxicity. Human reproduction (Oxford, England) 17 29309588
2018 The novel EHEC gene asa overlaps the TEGT transporter gene in antisense and is regulated by NaCl and growth phase. Scientific reports 17 30552341
2016 Effect of BI-1 on insulin resistance through regulation of CYP2E1. Scientific reports 16 27576594
2023 TMBIM6-mediated miR-181a expression regulates breast cancer cell migration and invasion via the MAPK/ERK signaling pathway. Journal of Cancer 14 37057283
2021 TMBIM6 regulates redox-associated posttranslational modifications of IRE1α and ER stress response failure in aging mice and humans. Redox biology 14 34562874
2020 Long non-coding RNA plasmacytoma variant translocation 1 (PVT1) promotes glioblastoma multiforme progression via regulating miR-1301-3p/TMBIM6 axis. European review for medical and pharmacological sciences 14 33275233
2016 Melatonin restricts Pb-induced PCD by enhancing BI-1 expression in tobacco suspension cells. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 14 27785728
2019 The characteristics of the ancient cell death suppressor, TMBIM6, and its related signaling pathways after endoplasmic reticulum stress. Journal of neuroscience research 13 31044452
2019 Expression of TMBIM6 in Cancers: The Involvement of Sp1 and PKC. Cancers 13 31336725
2019 Viral-mediated gene delivery of TMBIM6 protects the neonatal brain via disruption of NPR-CYP complex coupled with upregulation of Nrf-2 post-HI. Journal of neuroinflammation 13 31472686
2024 13-oxyingenol dodecanoate derivatives induce mitophagy and ferroptosis through targeting TMBIM6 as potential anti-NSCLC agents. European journal of medicinal chemistry 11 38552425
2022 Exosomes From Cancer-Associated Mesenchymal Stem Cells Transmit TMBIM6 to Promote the Malignant Behavior of Hepatocellular Carcinoma via Activating PI3K/AKT Pathway. Frontiers in oncology 11 35720012
2011 Comparison of Bi(1), Bi(3) and C(60) primary ion sources for ToF-SIMS imaging of patterned protein samples. Surface and interface analysis : SIA 11 21516225
2011 Fast oxygen exchange kinetics of pore-free Bi(1-x)Sr(x)FeO(3-δ) thin films. Physical chemistry chemical physics : PCCP 11 21858367
2010 Overexpression of Bax inhibitor-1 (BI-1) induces cell transformation in NIH3T3 cells. Cell biology international 11 20597862
1998 Preliminary characterization of the protein encoded by human testis-enhanced gene transcript (TEGT). Molecular membrane biology 11 10087504
2023 TMBIM6 deficiency leads to bone loss by accelerating osteoclastogenesis. Redox biology 10 37399733
2022 Hsa_circ_0001495 contributes to cervical cancer progression by targeting miR-526b-3p/TMBIM6/mTOR axis. Reproductive biology 10 35533615
2021 Photochemistry of Heteroleptic 1,4,5,8-Tetraazaphenanthrene- and Bi-1,2,3-triazolyl-Containing Ruthenium(II) Complexes. Inorganic chemistry 10 34612633
2019 An endoplasmic reticulum stress regulator, Tmbim6, modulates secretory stage of mice molar. Journal of cellular physiology 10 30963569
2011 Monoamine carboxylate transporters are involved in BI-1-associated cancer metastasis in HT1080 colon fibrosarcoma cells. International journal of oncology 10 21537843
2019 Synthesis of (Bi1- Sb )2S3 solid solutions via thermal decomposition of bismuth and antimony piperidinedithiocarbamates. RSC advances 9 35521396
2024 Structural Phase Transition in 0D (3,5-DMP)2Bi1-SbCl5 Metal Halides: Expression of the Lone Pair Effect and Polyhedral Distortion. Inorganic chemistry 7 38588023
2024 TMBIM6/BI-1 is an intracellular environmental regulator that induces paraptosis in cancer via ROS and Calcium-activated ERAD II pathways. Oncogene 6 39609612
2021 miR‑302d‑3p regulates the viability, migration and apoptosis of breast cancer cells through regulating the TMBIM6‑mediated ERK signaling pathway. Molecular medicine reports 6 34651659
2020 Promoting Electrocatalytic Activity and Stability via Er0.4Bi1.6O3-δ In Situ Decorated La0.8Sr0.2MnO3-δ Oxygen Electrode in Reversible Solid Oxide Cell. ACS applied materials & interfaces 6 33332091
2019 The in vivo antinociceptive and μ-opioid receptor activating effects of the combination of N-phenyl-2',4'-dimethyl-4,5'-bi-1,3-thiazol-2-amines and naloxone. European journal of medicinal chemistry 6 30776693
2016 Synthesis of two-dimensional Tl(x)Bi(1-x) compounds and Archimedean encoding of their atomic structure. Scientific reports 6 26781340
2024 CircRNA Arf3 suppresses glomerular mesangial cell proliferation and fibrosis in diabetic nephropathy via miR-107-3p/Tmbim6 axis. Journal of bioenergetics and biomembranes 5 39120858
2023 P3/P3N-PIPO of PVY interacting with BI-1 inhibits the degradation of NIb by ATG6 to facilitate virus replication in N. benthamiana. Frontiers in plant science 5 37139112
2021 TMBIM6, a potential virus target protein identified by integrated multiomics data analysis in SARS-CoV-2-infected host cells. Aging 5 33744846
2016 Synthesis and Study on Ionic Conductive (Bi1-x,Vx)O1.5-δ Materials with a Dual-Phase Microstructure. Materials (Basel, Switzerland) 5 28773981
2025 Transcription factor TCF3 promotes bladder cancer development via TMBIM6-Ca2+-dependent ferroptosis. Cell death discovery 4 40610429
2024 LncRNA SNHG1 acts as a ceRNA for miR-216a-3p to regulate TMBIM6 expression in esophageal squamous cell carcinoma. Journal of Cancer 4 38706912
2018 In Situ Formation of Er0.4Bi1.6O3 Protective Layer at Cobaltite Cathode/Y2O3-ZrO2 Electrolyte Interface under Solid Oxide Fuel Cell Operation Conditions. ACS applied materials & interfaces 4 30394736
2006 Determination of nucleic acids based on the quenching effect on resonance light scattering of the Y(III)-1,6-bi(1'-phenyl-3'-methyl-5'-pyrazolone-4'-)hexane-dione system. Luminescence : the journal of biological and chemical luminescence 4 16502393
2025 LPS-induced TMBIM6 splicing drives endothelial necroptosis and aggravates ALI. Respiratory investigation 3 39788046
2022 TMBIM6 promotes diabetic tubular epithelial cell survival and albumin endocytosis by inhibiting the endoplasmic reticulum stress sensor, IRE1α. Molecular biology reports 3 35857174
2020 Correction to: DNA‑PKcs promotes cardiac ischemia reperfusion injury through mitigating BI‑1‑governed mitochondrial homeostasis. Basic research in cardiology 3 32232579
2019 An in vivo and in silico analysis of novel variation in TMBIM6 gene affecting cardiopulmonary traits of Indian goats. Journal of thermal biology 3 32125979
2017 [Over-expressed Bax inhibitor 1 (BI-1) inhibits apoptosis of hippocampal neurons via endoplasmic reticulum IRE1-JNK pathway in rats with subarachnoid hemorrhage]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 3 29169414
2015 Structural defects as a factor controlling the magnetic properties of pure and Ti-doped Bi(1-x)Ca(x)FeO(3-x/2) multiferroics. Journal of physics. Condensed matter : an Institute of Physics journal 3 26447603
2025 Understanding the Relation between the Structure and Emission Properties in 0D (2-ABI)3Bi1-SbCl6·H2O: Impact of Structural Distortion and Stereoactivity of ns2 Lone Pairs. Inorganic chemistry 2 40063897
2025 Methyltransferase-like 14 (METTL14)-mediated N6-methyladenosine (m6A) Modification of Forkhead Box Protein 1 (FOXP1) Regulates Trophoblast Inflammation and Function via Transmembrane BAX Inhibitor Motif-Containing 6 (TMBIM6). Journal of biochemical and molecular toxicology 2 40852886
2015 Effects of Sb Content (x) on (Bi(1-x)Sb(x))2Te3 Thermoelectric Thin Film Deposited by Effusion Cell Evaporator. Journal of nanoscience and nanotechnology 2 26726497
2014 BI-1 enhances Fas-induced cell death through a Na+/H+-associated mechanism. BMB reports 2 24314142
2025 Deciphering the Function of lncRNA XIST/miR-329-3p/TMBIM6 Axis in the Proliferation of Non-Small Cell Lung Cancer. Journal of investigative surgery : the official journal of the Academy of Surgical Research 1 39950203
2025 CSDE1 regulates the miR-20a-5p/TMBIM6 axis in melanoma. RNA (New York, N.Y.) 1 41093770
2023 Effect of calcium doping on the electrocatalytic activity of the Bi1- Ca FeO3- oxygen electrode for solid oxide fuel cells. RSC advances 1 36741133
2022 Sulfur-Induced Vacancies in Ba2Bi1.4Nb0.6O6 Promoting Photocatalytic Tetracycline Hydrochloride Degradation. Inorganic chemistry 1 36516860
2012 Combinatorial gene targeting hTERT and BI-1 in CNE-2 nasopharyngeal carcinoma cell line. Biomedical reports 1 24648937
2026 Epitaxial Active Interface to Construct Intralattice-Bonded Asymmetric Bi1─O─Bi2 Sites for Robust CO2 Photoreduction to Acetic Acid. Angewandte Chemie (International ed. in English) 0 41491622
2026 TMBIM6 enhances dopaminergic neuron survival by modulating the IRE1a pathway in Parkinson's disease. Cell death & disease 0 41932887
2025 Stereochemical expression of Bi 6s2 lone pairs mediates fluoride-ion (De)insertion in tunnel-structured Bi2PdO4 and Bi1.6Pb0.4PtO4. Chemical science 0 39975768
2025 TMBIM6 promotes glioma progression according to integrated bioinformatics and experimental evidence. Scientific reports 0 40595030
2025 Design and simulation of the potential of lead-free Ag3Bi1.1I6.3 perovskite solar cells with different charge transport for energy enhancement. RSC advances 0 40761898
2025 Modulating the BI-1(TMBIM6)/AKT Signaling Pathway by Licochalcone D Treatment Inhibits Human Melanoma Cell Growth. Phytotherapy research : PTR 0 40944345
2025 The role of hsa_circ_0000520 in breast cancer progression: insights into the miR-542-3p/TMBIM6 regulatory axis. Cancer gene therapy 0 41413714
2023 Retraction: Exosomes from cancer-associated mesenchymal stem cells transmit TMBIM6 to promote the malignant behavior of hepatocellular carcinoma via activating PI3K/AKT pathway. Frontiers in oncology 0 37927479
2017 Crystal structure and absolute configuration of (3aR,3'aR,7aS,7'aS)-2,2,2',2'-tetra-methyl-3a,6,7,7a,3'a,6',7',7'a-octa-hydro-4,4'-bi[1,3-benzodioxol-yl], obtained from a Pd-catalyzed homocoupling reaction. Acta crystallographica. Section E, Crystallographic communications 0 28083142
2011 New Fe3+/Cr3+ perovskites with anomalous transport properties: the solid solution La(x)Bi(1-x)Fe(0.5)Cr(0.5)O3 (0.4 ≤ x ≤ 1). Inorganic chemistry 0 21786768
2009 Dielectric, piezoelectric, and ferroelectric properties of MnCO3-added 74(Bi(1/2)Na(1/2)) TiO3-20.8(Bi(1/2)K(1/2))TiO3-5.2BaTiO3 lead-free piezoelectric ceramics. IEEE transactions on ultrasonics, ferroelectrics, and frequency control 0 19473907

Missed literature

Know a paper Affinage missed for TMBIM6? Flag it for the maintainers and the community.

No submissions yet.