Affinage

TMIGD1

Transmembrane and immunoglobulin domain-containing protein 1 · UniProt Q6UXZ0

Length
262 aa
Mass
29.2 kDa
Annotated
2026-06-10
15 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMIGD1 is an immunoglobulin-superfamily cell adhesion molecule of renal tubular and intestinal epithelial cells that organizes the apical brush border and stabilizes epithelial barrier integrity through homophilic adhesion and PDZ/ERM-dependent scaffolding (PMID:26342724, PMID:36099341). Its extracellular domain mediates self-dimerization and supports transepithelial resistance, paracellular barrier function, and resistance to oxidative and nutrient-deprivation injury (PMID:26342724). At the proximal base of intestinal microvilli, TMIGD1 nucleates an intermicrovillar adhesion complex by binding the scaffolding proteins EBP50 and E3KARP, a complex whose assembly requires ezrin-mediated EBP50 activation and PP1α-dependent dephosphorylation of EBP50 Ser162; loss of TMIGD1 in enterocytes causes microvillar blebbing and defective brush border formation (PMID:36099341). Independently, a conserved cytoplasmic RRKK motif binds the N-terminal domains of the ERM proteins moesin and ezrin to direct their apical localization, suppress filopodia and migration, and promote α-tubulin Lys40 acetylation and mitotic spindle organization (PMID:34503512). The C-terminal PDZ-binding motif recruits the polarity protein Scribble to the lateral membrane—an interaction defined at atomic resolution with Scrib PDZ1—and also engages the mitochondrial outer-membrane protein SYNJ2BP, consistent with confluency-dependent partitioning of TMIGD1 between cell-cell contacts and mitochondria (PMID:37430142, PMID:32303178). In barrier defense, TMIGD1 binds BANF1 to suppress NF-κB activation and inflammation, and its enterocyte-specific deletion sensitizes mice to colitis (PMID:37542259). TMIGD1 acts as a tumor suppressor downstream of the transcription factor C/EBPβ/LAP, driving p38 MAPK signaling and induction of the cell-cycle inhibitors p21CIP1 and p27KIP1 (PMID:29515762). Its abundance is negatively controlled by oxidative-stress-induced ubiquitination and by macrophage exosomal miR-223 targeting its mRNA (PMID:26342724, PMID:37301121).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2015 Medium

    Established TMIGD1 as a functional epithelial adhesion molecule rather than an orphan Ig-domain protein by showing it self-dimerizes and controls barrier and migratory properties.

    Evidence Adhesion, TEER, permeability, and migration assays with overexpression/knockdown plus ubiquitination assays and kidney injury mouse models

    PMID:26342724

    Open questions at the time
    • Homophilic dimerization not validated by in vitro reconstitution or structure
    • Ubiquitination machinery (E3 ligase) not identified
  2. 2017 Medium

    Placed TMIGD1 in a growth-suppressive program by identifying its upstream transcriptional driver C/EBPβ/LAP and downstream p38 MAPK/p21/p27 axis in renal cancer.

    Evidence Promoter activity and Co-IP at the TMIGD1 promoter, re-expression in RCC cell lines, p38/p21/p27 Western blots, migration and branching assays

    PMID:29515762

    Open questions at the time
    • Mechanistic link between adhesion function and p38 signaling unresolved
    • No in vivo tumor genetics
  3. 2020 Medium

    Revealed confluency- and glycosylation-dependent dual targeting of TMIGD1 to mitochondria and cell-cell contacts and identified SYNJ2BP as the mitochondrial anchor.

    Evidence Subcellular fractionation, glycosylation inhibition, reciprocal Co-IP, domain mutagenesis, confocal co-localization

    PMID:32303178

    Open questions at the time
    • Functional consequence of mitochondrial localization not defined
    • How confluency triggers relocalization unknown
  4. 2020 Low

    Connected TMIGD1 to human disease by showing its apical enterocyte localization is lost in inflamed Crohn's disease mucosa and downregulated by hypoxia.

    Evidence Immunofluorescence on resection tissue, whole-transcriptome analysis, in vitro hypoxia

    PMID:32508154

    Open questions at the time
    • Descriptive localization without mechanistic follow-up
    • Causality between TMIGD1 loss and inflammation not tested here
  5. 2021 High

    Defined the cytoplasmic effector mechanism: TMIGD1 binds moesin/ezrin via an RRKK motif to control apical ERM localization, suppress filopodia/migration, and drive α-tubulin acetylation and spindle organization.

    Evidence Reciprocal Co-IP with RRKK mutagenesis, TMIGD1 mouse knockout localization, moesin CRISPR knockout epistasis, acetylated tubulin and migration readouts

    PMID:34503512

    Open questions at the time
    • Mechanism linking ERM binding to tubulin acetylation not resolved
    • Relevant tubulin acetyltransferase not identified
  6. 2021 Medium

    Extended TMIGD1's cytoprotective role beyond kidney by showing it preserves mitochondrial function and reduces apoptosis under oxidative stress in mesothelial cells.

    Evidence Overexpression with JC-1, ROS/MDA, TEM, apoptosis and adhesion assays, in vivo abdominal adhesion model

    PMID:34426761

    Open questions at the time
    • Molecular pathway linking TMIGD1 to mitochondrial protection unclear
    • Whether SYNJ2BP mediates this effect untested
  7. 2022 High

    Resolved the brush-border assembly mechanism: TMIGD1 forms a basal intermicrovillar adhesion complex with EBP50/E3KARP requiring ezrin activation and PP1α-mediated EBP50 dephosphorylation.

    Evidence Co-IP, pulldowns, PP1α phosphatase treatment, FRAP, enterocyte-specific Tmigd1 knockout mice with ultrastructural phenotype

    PMID:36099341

    Open questions at the time
    • Spatial coupling between basal TMIGD1 complex and tip protocadherin complex unknown
    • Upstream signals controlling PP1α activity here undefined
  8. 2023 High

    Provided the structural basis for TMIGD1 as a lateral-membrane anchor for the polarity machinery via its PDZ-binding motif engaging Scribble PDZ1.

    Evidence Co-IP, binding assays across all four Scrib PDZ domains, X-ray crystallography of the TMIGD1 peptide–Scrib PDZ1 complex, confocal localization

    PMID:37430142

    Open questions at the time
    • Functional consequence of Scrib mislocalization in TMIGD1-null cells not quantified
    • Competition between SYNJ2BP and Scrib for the same C-terminal motif not addressed
  9. 2023 High

    Identified an anti-inflammatory mechanism: TMIGD1 binds BANF1 to inhibit NF-κB and maintain barrier integrity, with knockout mice sensitized to colitis.

    Evidence Co-IP, GST pulldown, mass spectrometry, TEER/permeability, organoids, intestinal-specific Tmigd1 knockout mice, cytokine and omics profiling

    PMID:37542259

    Open questions at the time
    • How cytoplasmic BANF1 interaction translates to NF-κB suppression mechanistically unclear
    • Relationship to its junctional adhesion role not integrated
  10. 2023 Medium

    Showed TMIGD1 is post-transcriptionally repressed by macrophage exosomal miR-223, linking immune signaling to epithelial barrier loss in colitis.

    Evidence Exosomal miRNA sequencing, lentiviral miR-223 manipulation, DSS colitis model, mouse and human organoid–macrophage co-culture

    PMID:37301121

    Open questions at the time
    • Direct miR-223 binding site on TMIGD1 mRNA not mapped
    • Quantitative contribution relative to transcriptional and ubiquitin control unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TMIGD1's distinct interaction modules (homophilic adhesion, EBP50/ERM scaffolding, Scribble/SYNJ2BP PDZ engagement, BANF1/NF-κB control) are coordinated within a single cell, and whether any human Mendelian phenotype results from TMIGD1 loss, remain unresolved.
  • No integrated model of how one C-terminal PDZ motif partitions among competing partners
  • No germline human genetic disease association in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098631 cell adhesion mediator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1500931 Cell-Cell communication 2 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
BANF1CEBPBE3KARPEBP50EZRMSNSCRIBSYNJ2BP
Complex memberships
intermicrovillar adhesion complex (TMIGD1-EBP50/E3KARP-ezrin)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 TMIGD1 is a cell adhesion molecule expressed in renal tubular epithelial cells whose extracellular domain mediates self-dimerization (homophilic interaction); it regulates transepithelial electric resistance, paracellular permeability, cell migration, and cell morphology, and protects renal epithelial cells from oxidative- and nutrient-deprivation-induced cell injury. Hydrogen peroxide-induced oxidative stress downregulates TMIGD1 expression and targets it for ubiquitination. Cell-based adhesion assays, transepithelial electrical resistance (TEER) measurements, permeability assays, migration assays, overexpression/knockdown in renal epithelial cell lines, ubiquitination assays, acute kidney injury and hypertensive kidney disease mouse models The American journal of pathology Medium 26342724
2017 TMIGD1 acts as a tumor suppressor in renal cancer. C/EBPβ/LAP is a key transcriptional regulator that physically interacts with the TMIGD1 promoter and drives its expression; loss of C/EBPβ/LAP is responsible for TMIGD1 downregulation in RCC. Re-expression of TMIGD1 in renal tumor cells stimulates p38 MAPK phosphorylation and induces expression of cell-cycle inhibitors p21CIP1 and p27KIP1, inhibiting tumor growth and metastatic behaviors. Promoter activity assays, co-immunoprecipitation of C/EBPβ with TMIGD1 promoter, overexpression of TMIGD1 in renal tumor cell lines, Western blot for p38/p21/p27, migration and morphogenic branching assays Oncotarget Medium 29515762
2020 TMIGD1 localizes to mitochondria in subconfluent renal epithelial cells and to cell-cell contacts in confluent cells; this cell-confluency-regulated localization is modulated by N-glycosylation. Both the extracellular and cytoplasmic domains contribute to cell-cell contact localization. SYNJ2BP (a PDZ-domain-containing mitochondrial outer membrane protein) is a direct interaction partner of TMIGD1; the interaction is mediated by the PDZ domain of SYNJ2BP and the C-terminal PDZ domain-binding motif of TMIGD1, and SYNJ2BP can actively recruit TMIGD1 to mitochondria. Subcellular fractionation, immunofluorescence/confocal microscopy, glycosylation inhibition, co-immunoprecipitation, domain-deletion/mutation analysis, confocal co-localization BMC molecular and cell biology Medium 32303178
2021 TMIGD1 binds directly to ERM family proteins moesin and ezrin via an evolutionarily conserved RRKK motif on its C-terminus interacting with the N-terminal ERM domains. TMIGD1 governs the apical localization of moesin and ezrin in epithelial cells (loss of TMIGD1 in mice alters this localization). TMIGD1 inhibits moesin-induced filopodia-like protrusions and cell migration. TMIGD1 stimulates Lys40 acetylation of α-tubulin and promotes mitotic spindle organization; CRISPR/Cas9 knockout of moesin impairs TMIGD1-mediated α-tubulin acetylation and F-actin organization. Co-immunoprecipitation, domain-deletion/mutagenesis (RRKK motif), in vivo mouse knockout of TMIGD1, CRISPR/Cas9 knockout of moesin, immunofluorescence for moesin/ezrin localization, acetylated α-tubulin Western blot, migration assays, filopodia quantification Journal of biomedical science High 34503512
2021 TMIGD1 overexpression in peritoneal mesothelial cells protects against H2O2-induced oxidative stress injury by preserving mitochondrial function (assessed by JC-1 mitochondrial membrane potential, ROS/MDA levels, and transmission electron microscopy), reduces mesothelial cell apoptosis, and enhances mesothelial cell adhesion, thereby inhibiting postoperative abdominal adhesion formation in mice. TMIGD1-overexpressing cell line, MTT/apoptosis assays, ROS/MDA assays, JC-1 mitochondrial staining, immunofluorescence, transmission electron microscopy, scratch-wound/adhesion assays, in vivo mouse adhesion model Oxidative medicine and cellular longevity Medium 34426761
2022 TMIGD1 forms an intermicrovillar adhesion complex at the proximal base region of intestinal microvilli (distinct from the protocadherin-based tip complex). TMIGD1 directly interacts with microvillar scaffolding proteins EBP50 and E3KARP. Complex formation with EBP50 requires ezrin-mediated EBP50 activation and is enhanced by dephosphorylation of Ser162 in the PDZ2 domain of EBP50 by phosphatase PP1α. Binding of the EBP50-ezrin complex to TMIGD1 enhances the dynamic turnover of EBP50 at microvilli. Enterocyte-specific inactivation of Tmigd1 in mice causes microvillar blebbing, loss of intermicrovillar adhesion, and perturbed brush border formation. Co-immunoprecipitation, pulldown assays, phosphatase (PP1α) treatment, FRAP for EBP50 dynamics, enterocyte-specific Tmigd1 knockout mice, confocal and electron microscopy Science signaling High 36099341
2023 TMIGD1 directly interacts with cytoplasmic BAF nuclear assembly factor 1 (BANF1) and inhibits NF-κB activation. Knockdown of TMIGD1 in intestinal epithelial cells increases paracellular permeability, reduces TEER and apical junction complex expression, and induces pro-inflammatory cytokine production. Exogenous expression of TMIGD1 and BANF1 restores intestinal barrier function and inhibits inflammation both in vitro and in vivo. Intestinal-specific Tmigd1 knockout mice are more susceptible to chemically induced colitis. Co-immunoprecipitation, GST pull-down assays, mass spectrometry, TEER/permeability assays, organoid cultures, intestinal-specific Tmigd1 knockout (Tmigd1INT-KO) mice, cytokine measurements, transcriptome/proteomics analysis BMC medicine High 37542259
2023 TMIGD1 directly interacts with the polarity protein Scribble (Scrib) through a PDZ domain-mediated interaction and recruits Scrib to the lateral membrane domain in epithelial cells. The crystal structure of the TMIGD1 C-terminal peptide complexed with PDZ domain 1 of Scrib was determined, defining the structural basis of the interaction. TMIGD1 thus serves as a membrane anchor for Scrib. Co-immunoprecipitation, direct binding assays characterizing all four Scrib PDZ domains, X-ray crystallography (crystal structure of TMIGD1 C-terminal peptide with Scrib PDZ1), confocal immunofluorescence of membrane localization Communications biology High 37430142
2023 Macrophage-derived exosomal miR-223 targets TMIGD1 mRNA and inhibits its expression, promoting intestinal barrier dysfunction in DSS-induced colitis. Upregulated exosomal miR-223 from LPS-stimulated macrophages exacerbates colitis in vivo; this was verified using mouse and human colon organoids co-cultured with macrophages. miRNA sequencing of macrophage-derived exosomes, lentiviral miR-223 overexpression/inhibition, DSS-induced mouse colitis model, mouse and human organoid co-culture with macrophages in Transwell system, qPCR/Western blot for TMIGD1 International immunopharmacology Medium 37301121
2020 TMIGD1 localizes to the apical microvilli of well-differentiated enterocytes (but not intestinal crypt cells), and this apical localization is reduced in noninflamed and nearly absent in inflamed CD mucosa. Hypoxia decreases TMIGD1 expression in enterocyte-like cells in vitro. Immunofluorescence on surgical resection tissue and enterocyte-like cell cultures, whole transcriptome gene expression analysis, in vitro hypoxia experiments American journal of physiology. Gastrointestinal and liver physiology Low 32508154

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 Macrophage-derived exosomes promote intestinal mucosal barrier dysfunction in inflammatory bowel disease by regulating TMIGD1 via mircroRNA-223. International immunopharmacology 29 37301121
2015 TMIGD1 is a novel adhesion molecule that protects epithelial cells from oxidative cell injury. The American journal of pathology 28 26342724
2023 Decreased TMIGD1 aggravates colitis and intestinal barrier dysfunction via the BANF1-NF-κB pathway in Crohn's disease. BMC medicine 22 37542259
2020 The mitochondrial outer membrane protein SYNJ2BP interacts with the cell adhesion molecule TMIGD1 and can recruit it to mitochondria. BMC molecular and cell biology 21 32303178
2017 TMIGD1 acts as a tumor suppressor through regulation of p21Cip1/p27Kip1 in renal cancer. Oncotarget 18 29515762
2022 Intestinal brush border formation requires a TMIGD1-based intermicrovillar adhesion complex. Science signaling 14 36099341
2020 Transcriptomic identification of TMIGD1 and its relationship with the ileal epithelial cell differentiation in Crohn's disease. American journal of physiology. Gastrointestinal and liver physiology 14 32508154
2021 TMIGD1 Inhibited Abdominal Adhesion Formation by Alleviating Oxidative Stress in the Mitochondria of Peritoneal Mesothelial Cells. Oxidative medicine and cellular longevity 13 34426761
2021 The cell adhesion molecule TMIGD1 binds to moesin and regulates tubulin acetylation and cell migration. Journal of biomedical science 11 34503512
2023 TMIGD1: Emerging functions of a tumor supressor and adhesion receptor. Oncogene 5 37087524
2022 The Role of TMIGD1 as a Tumor Suppressor in Colorectal Cancer. Genetic testing and molecular biomarkers 5 35481970
2023 Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1. Communications biology 3 37430142
2018 A new DNA marker of the TMIGD1 gene used to identify high fertilization rates in Tsaiya ducks (Anas platyrhynchos). The Journal of reproduction and development 2 30305481
2018 A new method for detection of single nucleotide polymorphism in a female reproduction-associated gene, tmigd1, of Anas platyrhynchos using a strip biosensor with gold nanoparticles. Poultry science 1 29945164
2025 Human TMIGD1 Promoter Exhibits Robust Activity in Prokaryotic Cells. Biochemistry 0 41439483

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