Affinage

TMEFF1

Tomoregulin-1 · UniProt Q8IYR6

Length
380 aa
Mass
40.9 kDa
Annotated
2026-06-10
12 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEFF1 is a single-pass transmembrane protein with a dual role as a regulator of developmental signaling and a neuronal restriction factor for herpes simplex virus (PMID:14563676, PMID:39048830). Through its extracellular N-terminal domain, TMEFF1 interacts with cell-surface NECTIN-1 and impairs HSV-1 glycoprotein D- and NECTIN-1-mediated virus-cell membrane fusion, blocking viral entry; this domain alone confers HSV-1 resistance even in non-neuronal NECTIN-1-expressing cells, and TMEFF1 additionally associates with non-muscle myosin heavy chains IIA and IIB (PMID:39048823, PMID:39048830). Loss of TMEFF1 elevates viral replication and neuronal death in iPSC-derived neurons and increases HSV-1 susceptibility in brain neurons of knockout mice, and biallelic rare deleterious TMEFF1 variants underlie herpes simplex encephalitis in patients (PMID:39048823, PMID:39048830). Independently of its antiviral role, TMEFF1 inhibits nodal signaling by directly binding the nodal coreceptor Cripto via the same CFC domain that Cripto uses for ALK4 receptor engagement, without itself contacting nodal or ALK4 (PMID:14563676). TMEFF1 transcription is controlled by Smad2/3 downstream of TGF-β and by miR-592-3p in neurons (PMID:38519646, PMID:35020881). In several cancer contexts its expression engages MAPK and PI3K/AKT signaling and drives EMT, proliferation, migration, and invasion (PMID:30697076, PMID:34475991).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2003 High

    Established the first molecular mechanism for TMEFF1 by showing it antagonizes nodal/TGF-β-family signaling not at the ligand or type I receptor level but by sequestering the Cripto coreceptor.

    Evidence Co-immunoprecipitation and Xenopus ectodermal explant rescue with wild-type versus CFC-domain-mutant Cripto

    PMID:14563676

    Open questions at the time
    • Does not establish the structural basis of the TMEFF1-Cripto interface
    • Mammalian developmental relevance not tested
    • Did not link nodal antagonism to a physiological process in vivo
  2. 2003 Medium

    Defined TMEFF1 as a membrane-localized protein and gave a first functional hint of growth suppression in brain tumor cells.

    Evidence EGFP fusion imaging and ectopic overexpression growth assays in brain cancer cells

    PMID:12743596

    Open questions at the time
    • Mechanism of growth inhibition unresolved
    • Single-lab overexpression phenotype
    • No endogenous loss-of-function validation
  3. 2019 Medium

    Connected TMEFF1 to oncogenic signaling output, showing its overexpression activates MAPK and PI3K/AKT and drives EMT, with p53 binding the promoter to control its expression in ovarian cancer.

    Evidence Overexpression/knockdown assays, Western blot, pathway inhibitor rescue, and ChIP for p53 at the TMEFF1 promoter

    PMID:30697076

    Open questions at the time
    • Mechanism linking a transmembrane protein to MAPK/AKT activation not defined
    • Single cancer-cell-line context
    • Direct versus indirect p53 regulation not dissected
  4. 2021 Medium

    Showed the pro-invasive, pathway-activating role of TMEFF1 extends to endometrial carcinoma but that its transcriptional control is context-dependent, with p53 not binding the promoter here.

    Evidence siRNA knockdown with migration/invasion assays, EMT and pathway Western blots, and a negative p53 ChIP

    PMID:34475991

    Open questions at the time
    • Identity of the operative transcriptional regulator in this tissue unknown
    • Single-lab observation
    • Reason for tissue-specific p53 behavior unexplained
  5. 2022 Medium

    Identified a post-transcriptional control point for neuronal TMEFF1, with miR-592-3p tuning its protein level and behaviorally relevant output.

    Evidence Dual-luciferase reporter assay plus stereotactic miRNA gain/loss-of-function in mouse nucleus accumbens with behavioral and Western readout

    PMID:35020881

    Open questions at the time
    • Downstream neuronal effector of TMEFF1 in craving unknown
    • Single-lab study
    • Molecular function of TMEFF1 in neurons not linked to the behavior mechanistically
  6. 2024 Medium

    Placed TMEFF1 in a TGF-β/Smad2/3 transcriptional circuit, showing Parkin loss raises TGF-β, activating Smad2/3 that binds the TMEFF1 promoter to drive pro-metastatic EMT in liver cancer.

    Evidence shRNA knockdown, TGF-β inhibitor rescue, ChIP for Smad2/3 at the TMEFF1 promoter, and Co-IP for Parkin partners

    PMID:38519646

    Open questions at the time
    • Direct effector function of TMEFF1 protein downstream of induction not shown
    • Single-lab model
    • Whether Smad2/3 control of TMEFF1 generalizes beyond liver cancer untested
  7. 2024 High

    Defined TMEFF1's principal physiological function as a cell-autonomous neuronal restriction factor for HSV-1, acting through NECTIN-1 binding and inhibition of gD/NECTIN-1-mediated fusion, with its extracellular domain sufficient and human deficiency causing herpes simplex encephalitis.

    Evidence Genome-wide CRISPR screen, iPSC-derived neuron depletion, NECTIN-1/myosin interaction assays, Tmeff1-/- mouse viral challenge, patient genetics, domain-deletion constructs, and type I IFN rescue

    PMID:39048823 PMID:39048830

    Open questions at the time
    • Structural basis of the TMEFF1-NECTIN-1 fusion-blocking interaction not resolved
    • Functional role of myosin IIA/IIB association not dissected
    • Whether antiviral and nodal-antagonist functions are mechanistically linked unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single transmembrane protein reconciles its distinct roles in Cripto/nodal antagonism, HSV-1 restriction via NECTIN-1, and cancer MAPK/AKT/EMT signaling, and what its direct intracellular effectors are, remains unresolved.
  • No structural model of any TMEFF1 interaction
  • No unifying biochemical activity assigned to the protein
  • Intracellular signaling partners undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
CRIPTOMYH10MYH9NECTIN1

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TMEFF1 inhibits nodal signaling by directly binding to the nodal coreceptor Cripto, but does not associate with nodal itself or the type I ALK4 receptor. The CFC domain of Cripto, essential for ALK4 binding, is also required for TMEFF1 interaction. Rescue experiments in Xenopus ectodermal explants with wild-type but not CFC-domain mutant Cripto confirmed this mechanism. Co-immunoprecipitation, Xenopus ectodermal explant rescue assays with wild-type and mutant Cripto Genes & development High 14563676
2024 TMEFF1 blocks HSV-1 entry into neurons by interacting with nectin-1 (the core HSV-1 cell-surface receptor) and non-muscle myosin heavy chains IIA and IIB (involved in virus-cell fusion). Depletion of TMEFF1 in stem-cell-derived human neurons elevated viral replication and neuronal death. Tmeff1-/- mice showed increased HSV-1 susceptibility specifically in brain neurons. Genome-wide CRISPR screen, TMEFF1 depletion in iPSC-derived neurons, protein interaction assays, Tmeff1-/- mouse model with viral challenge Nature High 39048823
2024 TMEFF1 interacts with cell-surface NECTIN-1 and impairs HSV-1 glycoprotein D- and NECTIN-1-mediated virus-cell membrane fusion, blocking viral entry into cortical neurons. The extracellular N-terminal domain (but not the intracellular C-terminal domain) is sufficient to confer HSV-1 resistance even in non-neuronal NECTIN-1-expressing cells. TMEFF1 deficiency (homozygous rare deleterious variants) in two unrelated patients underlies herpes simplex encephalitis. Patient genetics, CRISPR-Cas9-engineered human pluripotent stem cell-derived cortical neurons, viral entry assays, domain-deletion constructs, type I IFN rescue experiments Nature High 39048830
2003 TMEFF1 fused to EGFP localizes to the cell membrane, consistent with its transmembrane domain architecture. Ectopic expression of TMEFF1 in brain cancer cells causes growth inhibition. EGFP fusion protein imaging, ectopic overexpression with cell growth assay Oncogene Medium 12743596
2019 TMEFF1 overexpression in ovarian cancer cells activates MAPK and PI3K/AKT signaling pathways, promoting proliferation, migration, invasion, and EMT (decreased E-cadherin; increased vimentin and N-cadherin). The transcription factor p53 binds the TMEFF1 gene promoter region and regulates TMEFF1 protein expression, as shown by ChIP and Western blot. Overexpression/knockdown cell assays, Western blot for pathway phosphoproteins and EMT markers, ChIP assay for p53 binding at TMEFF1 promoter, pathway inhibitor experiments Cancer management and research Medium 30697076
2024 Parkin deficiency leads to upregulation of TGF-β production, which activates Smad2/3 phosphorylation; phosphorylated Smad2/3 binds the TMEFF1 promoter to drive TMEFF1 transcription, promoting liver cancer cell migration, EMT, and metastasis. TGF-β inhibitor and TMEFF1 knockdown both reverse shParkin-induced migration. Parkin also interacts with and promotes ubiquitin-dependent degradation of HIF-1α/HIF-1β and p53, suppressing TGF-β production. shRNA knockdown, TGF-β inhibitor rescue, ChIP for Smad2/3 binding at TMEFF1 promoter, co-immunoprecipitation for Parkin-HIF-1α/HIF-1β/p53 interaction, Western blot Acta pharmacologica Sinica Medium 38519646
2021 Knockdown of TMEFF1 in endometrial carcinoma cells inhibits cell invasion and migration, suppresses EMT, and reduces activation of MAPK and PI3K/AKT pathways. In contrast to ovarian cancer, ChIP assay showed that p53 does NOT bind the TMEFF1 promoter region in endometrial carcinoma cells. siRNA knockdown, scratch/Transwell assays, Western blot for EMT and pathway markers, ChIP assay (negative result for p53) Journal of Cancer Medium 34475991
2022 miR-592-3p targets TMEFF1 mRNA: a dual-luciferase assay confirmed miR-592-3p binding sites in TMEFF1. Inhibition of miR-592-3p in the nucleus accumbens core increased TMEFF1 protein expression and enhanced incubation of morphine craving in mice; overexpression of miR-592-3p decreased TMEFF1 expression and reduced craving behavior. Dual-luciferase reporter assay, stereotactic miRNA gain/loss-of-function in mouse NAc, Western blot for TMEFF1 protein The international journal of neuropsychopharmacology Medium 35020881

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Tomoregulin-1 (TMEFF1) inhibits nodal signaling through direct binding to the nodal coreceptor Cripto. Genes & development 59 14563676
2023 CircTmeff1 Promotes Muscle Atrophy by Interacting with TDP-43 and Encoding A Novel TMEFF1-339aa Protein. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 46 37088818
2001 Expression of TMEFF1 mRNA in the mouse central nervous system: precise examination and comparative studies of TMEFF1 and TMEFF2. Brain research. Molecular brain research 25 11165370
2024 TMEFF1 is a neuron-specific restriction factor for herpes simplex virus. Nature 24 39048823
2003 TMEFF1 and brain tumors. Oncogene 23 12743596
2024 Human TMEFF1 is a restriction factor for herpes simplex virus in the brain. Nature 22 39048830
2022 MIR503HG impeded ovarian cancer progression by interacting with SPI1 and preventing TMEFF1 transcription. Aging 16 35771155
2019 TMEFF1 overexpression and its mechanism for tumor promotion in ovarian cancer. Cancer management and research 14 30697076
2024 Parkin deficiency promotes liver cancer metastasis by TMEFF1 transcription activation via TGF-β/Smad2/3 pathway. Acta pharmacologica Sinica 10 38519646
2020 Butorphanol Inhibits the Malignant Biological Behaviors of Ovarian Cancer Cells via Down-Regulating the Expression of TMEFF1. OncoTargets and therapy 10 33149612
2022 Roles of miR-592-3p and Its Target Gene, TMEFF1, in the Nucleus Accumbens During Incubation of Morphine Craving. The international journal of neuropsychopharmacology 9 35020881
2021 Overexpression of TMEFF1 in Endometrial Carcinoma and the Mechanism Underlying its Promotion of Malignant Behavior in Cancer Cells. Journal of Cancer 6 34475991

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