Affinage

ILDR1

Immunoglobulin-like domain-containing receptor 1 · UniProt Q86SU0

Length
546 aa
Mass
62.8 kDa
Annotated
2026-06-10
23 papers in source corpus 12 papers cited in narrative 12 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

ILDR1 (angulin-2) is a type I transmembrane protein that localizes to tricellular tight junctions (tTJs) at tricellular epithelial contacts, where it recruits tricellulin and establishes a strong paracellular barrier (PMID:23239027). Through its Ig-like domain it organizes tTJ ultrastructure, and most DFNB42 deafness-causing mutations abolish tricellulin recruitment, while a domain variant predicted to disrupt homo-trimer formation causes only partial mislocalization (PMID:23239027, PMID:25668204). In the cochlea, ILDR1 is dispensable for the initial recruitment of tricellulin but is required to maintain its correct distribution along tricellular contacts and to preserve tTJ architecture; its loss causes progressive degeneration of cochlear hair cells and severe deafness despite a normal endocochlear potential (PMID:25217574, PMID:25819842). ILDR1 function is required in multiple inner ear cell types, as combined AAV delivery to both the organ of Corti and the cochlear lateral wall is needed to restore structure and auditory function (PMID:37481704). In the kidney, ILDR1 at distal tubule tTJs specifically restricts paracellular water permeability without affecting ionic permeability, and its loss produces a renal concentrating defect with polyuria and polydipsia (PMID:28461473). Loss of ILDR1 triggers tissue-specific compensatory redistribution of angulin-1/LSR to tricellular contacts, which restores barrier function in the intestine but not all ILDR1-specific functions elsewhere (PMID:25822906, PMID:32587380). Beyond its junctional role, ILDR1 binds the pre-mRNA splicing factors TRA2A, TRA2B and SRSF1 and translocates to the nucleus to modulate alternative splicing of target transcripts (PMID:28785060), promotes influenza A virus replication by competitively binding the antiviral scramblase PLSCR1 (PMID:35595813), and acts in cholecystokinin-positive enteroendocrine cells to mediate fat-stimulated CCK secretion and systemic metabolic regulation (PMID:35749484).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2012 High

    Established ILDR1's core molecular role: where it sits in the epithelium and how it builds a barrier, answering what the DFNB42 deafness gene actually does at the junction.

    Evidence Immunofluorescence localization and barrier assays in cultured epithelial cells expressing wild-type and DFNB42 mutant ILDR1

    PMID:23239027

    Open questions at the time
    • Did not resolve the in vivo requirement versus dispensability for tricellulin recruitment
    • Structural basis of tricellulin recruitment not defined
  2. 2014 High

    Distinguished initial recruitment from maintenance in vivo, showing ILDR1 is needed to sustain tTJ ultrastructure and hair cell survival rather than to seed tricellulin.

    Evidence Ildr1 knockout mouse with immunofluorescence, freeze-fracture EM, ABR and endocochlear potential measurement

    PMID:25217574

    Open questions at the time
    • Mechanism linking tTJ disruption to hair cell death not defined
    • Molecular partners maintaining ultrastructure unknown
  3. 2014 Medium

    Defined an ILDR1 ortholog function in inner ear and lateral line development, linking it to Na+/K+-ATPase and FGF/chemokine signaling during morphogenesis.

    Evidence ildr1b morpholino knockdown in zebrafish with atp1b2b mRNA rescue, in situ hybridization and behavioral assays

    PMID:24990150

    Open questions at the time
    • Morpholino knockdown not confirmed by genetic mutant
    • Direct biochemical link between ILDR1 and atp1b2b/FGF signaling not established
  4. 2015 High

    Revealed that loss of ILDR1 triggers compensatory angulin-1/LSR redistribution yet leaves ILDR1-specific functions unfilled, showing angulins are not fully interchangeable.

    Evidence Ildr1 knockout mouse immunofluorescence and ABR testing in organ of Corti

    PMID:25822906

    Open questions at the time
    • The ILDR1-specific function that LSR cannot substitute is not molecularly identified
  5. 2015 Medium

    Connected ILDR1 deficiency to a defined temporal course of outer hair cell degeneration and a broad proteomic signature, framing the downstream cellular consequences of tTJ failure.

    Evidence Ildr1 knockout mouse with immunofluorescence, SEM and 2D-DIGE/MS differential proteomics

    PMID:25819842

    Open questions at the time
    • Causal drivers among the dysregulated proteins not identified
    • Proteomic changes are correlative
  6. 2015 Medium

    Linked the ILDR1 Ig-like domain to homo-trimer formation as the structural basis for tricellulin recruitment, explaining a partial-phenotype variant.

    Evidence Cell-based localization of mutant proteins in LSR-knockdown cells plus 3D protein modeling

    PMID:25668204

    Open questions at the time
    • Homo-trimer model is computational only, not structurally confirmed
    • Oligomerization state in vivo unmeasured
  7. 2017 High

    Defined a specific physiological output of ILDR1 barriers: selective restriction of paracellular water but not ions in the renal distal tubule, explaining a urinary concentrating function.

    Evidence Ildr1 knockout mouse, live renal tubule microperfusion water permeability assays and overexpression in cultured renal cells

    PMID:28461473

    Open questions at the time
    • Molecular mechanism by which ILDR1 selectively blocks water flux unknown
    • Whether this is a direct property of the tTJ or indirect not resolved
  8. 2017 Medium

    Uncovered an unexpected nuclear role: ILDR1 binds splicing factors and modulates alternative splicing, expanding its function beyond junctions.

    Evidence Co-immunoprecipitation, nuclear translocation assays, siRNA knockdown and RT-PCR splicing readouts in cultured cells

    PMID:28785060

    Open questions at the time
    • Single lab; reciprocal validation and structural basis of splicing-factor binding absent
    • How a transmembrane protein accesses the nucleus mechanistically unclear
    • Physiological relevance of splicing changes untested in vivo
  9. 2020 Medium

    Demonstrated tissue-specific compensation, with LSR redistribution fully restoring intestinal barrier function while the kidney phenotype persists.

    Evidence Ildr1 knockout mouse Ussing chamber measurements and immunofluorescence in large intestine and kidney

    PMID:32587380

    Open questions at the time
    • Why compensation succeeds in intestine but not kidney not mechanistically explained
  10. 2022 Medium

    Identified ILDR1 as a proviral host factor that competitively binds PLSCR1 to disable its antiviral activity during influenza A infection.

    Evidence Yeast two-hybrid, Co-IP, Plscr1 knockout mouse infection and ILDR1 overexpression/knockdown in cells

    PMID:35595813

    Open questions at the time
    • Single lab; binding interface and stoichiometry of competition not defined
    • Relationship to ILDR1's junctional role unknown
  11. 2022 Medium

    Placed ILDR1 in enteroendocrine signaling, showing it mediates fat-stimulated CCK secretion and influences systemic metabolism.

    Evidence Ildr1 knockout mouse with metabolic chambers, hormone ELISA, glucose/insulin tolerance tests and ex vivo islet perifusion

    PMID:35749484

    Open questions at the time
    • Molecular mechanism by which ILDR1 couples fat sensing to CCK release not defined
    • Single lab
  12. 2023 Medium

    Established that ILDR1 is required in multiple cochlear cell types by achieving functional rescue only when both organ of Corti and lateral wall are targeted.

    Evidence Dual-tropism AAV delivery of Ildr1 cDNA in Ildr1 knockout mice with ABR and cochlear histology

    PMID:37481704

    Open questions at the time
    • Cell-type-specific molecular requirements not dissected
    • Durability and translational scope of rescue not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how a single tricellular junctional protein mechanistically integrates its barrier, nuclear splicing, antiviral, and enteroendocrine roles, and what structural features govern its selective control of water permeability.
  • No experimental structure of ILDR1 or its complexes
  • Mechanistic link between transmembrane localization and nuclear splicing function unresolved
  • Selective water-versus-ion barrier mechanism undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
GO:0005215 transporter activity 1
Partners
PLSCR1SRSF1TRA2ATRA2B
Complex memberships
tricellular tight junction

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 ILDR1 (angulin-2) localizes to tricellular tight junctions (tTJs) at tricellular contacts in epithelial cells and recruits tricellulin to tTJs. Introduction of ILDR1 into cultured epithelial cells establishes a strong paracellular barrier. Most DFNB42-associated ILDR1 mutant proteins are defective in tricellulin recruitment. Immunofluorescence localization, epithelial barrier function assays in cultured cells (EpH4), expression of DFNB42 mutant proteins Journal of cell science High 23239027
2014 In ILDR1 null mice, ILDR1 is not required for initial recruitment of tricellulin to tTJs in the cochlea in vivo; however, tricellulin becomes mislocalized in inner ear sensory epithelia after the first postnatal week. ILDR1 contributes to the ultrastructure of tTJs as revealed by freeze-fracture electron microscopy. Loss of ILDR1 causes rapid degeneration of cochlear hair cells and severe deafness, with normal endocochlear potential. Ildr1 knockout mouse analysis, immunofluorescence, freeze-fracture electron microscopy, auditory brainstem response, endocochlear potential measurement Human molecular genetics High 25217574
2015 In Ildr1 null mice, tricellulin localization at tricellular contacts of the organ of Corti is retained but its distribution along the depth of tricellular contacts is altered. Compensatory localization of angulin-1/LSR to tricellular contacts occurs in the organ of Corti of Ildr1 null mice, where it is barely detected in wild-type. Angulin-2/ILDR1 has distinct functions beyond tricellulin recruitment that cannot be substituted by angulin-1/LSR. Ildr1 knockout mouse, immunofluorescence, auditory brainstem response testing PloS one High 25822906
2015 A novel ILDR1 variant (p.P69H) in the Ig-like domain causes partial mislocalization of ILDR1 and tricellulin at tricellular contacts, in contrast to complete failure seen with other DFNB42 mutations. Three-dimensional protein modeling predicted that ILDR1 forms a homo-trimer through its Ig-like domain and that p.P69H disturbs homo-trimer formation. Expression of mutant proteins in angulin-1/LSR knockdown epithelial cells, immunofluorescence, 3D protein modeling PloS one Medium 25668204
2017 ILDR1 binds to pre-mRNA splicing factors TRA2A, TRA2B, and SRSF1 and translocates into the nucleus when these splicing factors are present. ILDR1 affects alternative splicing of TUBD1, IQCB1, and Pcdh19. Knockdown of endogenous ILDR1 (and ILDR2) by siRNA in cultured cells alters alternative splicing of TUBD1 and IQCB1. Co-immunoprecipitation, nuclear translocation assays, siRNA knockdown, RT-PCR-based splicing assays, yeast two-hybrid (implicit from context) Scientific reports Medium 28785060
2017 ILDR1 is localized to tricellular tight junctions of distal tubules in the mouse kidney. Genetic knockout of Ildr1 causes polyuria and polydipsia due to renal concentrating defects. Live microperfusion of renal distal tubules shows they are impermeable to water normally but become highly permeable to water in Ildr1 knockout animals, while paracellular ionic permeabilities are not affected. Overexpression of Ildr1 in cultured renal epithelial cells significantly reduces paracellular water permeability. Ildr1 knockout mouse, immunofluorescence localization, live renal tubule microperfusion, water permeability assays, overexpression in cultured cells Proceedings of the National Academy of Sciences of the United States of America High 28461473
2020 In the large intestine of Ildr1 knockout mice, angulin-1/LSR redistributes to tricellular tight junctions (compensating for loss of ILDR1), and paracellular transport assessed by Ussing chamber is unchanged. ILDR1 knockout mice show no detectable intestinal water transport phenotype. A similar LSR compensatory shift occurs in the kidney of Ildr1 knockout mice. Ildr1 knockout mouse, Ussing chamber measurements, immunofluorescence Scientific reports Medium 32587380
2022 ILDR1 promotes influenza A virus replication by binding to phospholipid scramblase 1 (PLSCR1), an antiviral protein. ILDR1 competes with viral NP protein for binding to PLSCR1, thereby inhibiting PLSCR1's antiviral activity. ILDR1 cannot directly interact with viral NP protein but competitively binds PLSCR1. Yeast two-hybrid screening, Co-immunoprecipitation, Plscr1 knockout mouse infection experiments, ILDR1 overexpression/knockdown in cell culture Scientific reports Medium 35595813
2022 ILDR1 is expressed in cholecystokinin-positive enteroendocrine cells of the gastrointestinal tract and mediates fat-stimulated CCK secretion. Ildr1 knockout mice on a high-fat diet gain less weight, have smaller adipocytes, increased metabolic activity, improved insulin sensitivity, and enhanced glucose-regulated insulin secretion compared to wild-type mice. Ildr1 knockout mouse, CLAMS metabolic chambers, ELISA hormone measurements, oral glucose tolerance test, insulin tolerance test, ex vivo islet perifusion, confocal microscopy PloS one Medium 35749484
2014 In zebrafish, ildr1b morpholino knockdown causes defective hearing, imbalanced swimming, and developmental delays in semicircular canal formation. Down-regulation of atp1b2b (Na+/K+-ATPase beta-2b subunit) was identified in ildr1b morphants, and injection of atp1b2b mRNA rescues the semicircular canal developmental delay phenotype. ildr1b knockdown also reduces lateral line neuromast numbers by disrupting posterior lateral line primordium migration, associated with attenuated FGF signaling and altered cxcr4b/cxcr7b expression. Morpholino knockdown in zebrafish, hearing/behavior assays, in situ hybridization, mRNA rescue experiments, gene expression profiling Human molecular genetics Medium 24990150
2023 Combined delivery of two AAVs with different tropism (AAV2.7m8 targeting organ of Corti; AAV8BP2 targeting cochlear lateral wall) delivering Ildr1 cDNA to Ildr1w-/- mice improves cochlear structural integrity and auditory function, demonstrating that ILDR1 function is required in multiple inner ear cell types. AAV-mediated gene therapy in Ildr1 knockout mouse, auditory brainstem response, cochlear histology Molecular therapy Medium 37481704
2015 ILDR1 deficiency causes progressive degeneration of outer hair cells beginning at postnatal day 15, with disruption of the tunnel of Corti by P21 and complete loss of OHCs by P28. ILDR1 deficiency affects tricellulin expression in vivo. Differential proteomics identified 708 upregulated and 114 downregulated proteins in Ildr1-/- cochleae, including proteins involved in cell adhesion, vesicle transport, cell death, and membrane organization. Ildr1 knockout mouse, immunofluorescence, scanning electron microscopy, differential proteomics (2D-DIGE/MS) Biology open Medium 25819842

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Analysis of the 'angulin' proteins LSR, ILDR1 and ILDR2--tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis. Journal of cell science 175 23239027
2011 Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42. American journal of human genetics 89 21255762
2019 Targeted Next Generation Sequencing Revealed a Novel Homozygous Loss-of-Function Mutation in ILDR1 Gene Causes Autosomal Recessive Nonsyndromic Sensorineural Hearing Loss in a Chinese Family. Frontiers in genetics 76 30804975
2014 ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells. Human molecular genetics 50 25217574
2015 Deficiency of angulin-2/ILDR1, a tricellular tight junction-associated membrane protein, causes deafness with cochlear hair cell degeneration in mice. PloS one 31 25822906
2017 ILDR1 is important for paracellular water transport and urine concentration mechanism. Proceedings of the National Academy of Sciences of the United States of America 27 28461473
2015 ILDR1 deficiency causes degeneration of cochlear outer hair cells and disrupts the structure of the organ of Corti: a mouse model for human DFNB42. Biology open 20 25819842
2014 ILDR1: Novel mutation and a rare cause of congenital deafness in the Saudi Arabian population. European journal of medical genetics 18 24768815
2017 Angulin proteins ILDR1 and ILDR2 regulate alternative pre-mRNA splicing through binding to splicing factors TRA2A, TRA2B, or SRSF1. Scientific reports 17 28785060
2015 Downsloping high-frequency hearing loss due to inner ear tricellular tight junction disruption by a novel ILDR1 mutation in the Ig-like domain. PloS one 16 25668204
2005 A novel autosomal recessive nonsyndromic hearing impairment locus (DFNB42) maps to chromosome 3q13.31-q22.3. American journal of medical genetics. Part A 15 15641023
2023 Combined AAV-mediated gene replacement therapy improves auditory function in a mouse model of human DFNB42 deafness. Molecular therapy : the journal of the American Society of Gene Therapy 11 37481704
2017 Next-generation sequencing identifies three novel missense variants in ILDR1 and MYO6 genes in an Iranian family with hearing loss with review of the literature. International journal of pediatric otorhinolaryngology 11 29224747
2014 Ildr1b is essential for semicircular canal development, migration of the posterior lateral line primordium and hearing ability in zebrafish: implications for a role in the recessive hearing impairment DFNB42. Human molecular genetics 11 24990150
2022 ILDR1 promotes influenza A virus replication through binding to PLSCR1. Scientific reports 10 35595813
2017 Diverse pattern of gap junction beta-2 and gap junction beta-4 genes mutations and lack of contribution of DFNB21, DFNB24, DFNB29, and DFNB42 loci in autosomal recessive nonsyndromic hearing loss patients in Hormozgan, Iran. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences 10 28900455
2020 Angulin-2/ILDR1, a tricellular tight junction protein, does not affect water transport in the mouse large intestine. Scientific reports 7 32587380
2017 Identification of a novel frameshift mutation in the ILDR1 gene in a UAE family, mutations review and phenotype genotype correlation. PloS one 7 28945813
2012 A new recurrent chromosomal translocation t(3;11)(q13;q14) in myelodysplastic syndromes associated with overexpression of the ILDR1 gene. Leukemia research 5 22365942
2018 A Novel p.G141R Mutation in ILDR1 Leads to Recessive Nonsyndromic Deafness DFNB42 in Two Chinese Han Families. Neural plasticity 4 29849566
2022 Ildr1 gene deletion protects against diet-induced obesity and hyperglycemia. PloS one 3 35749484
2017 Discovering the Unexpected with the Utilization of NGS in Diagnostics of Non-syndromic Hearing Loss Disorders: The Family Case of ILDR1-Dependent Hearing Loss Disorder. Frontiers in genetics 3 28713423
2023 Imputation of SNPs associated with presbycusis through linkage disequilibrium analysis in the ILDR1 gene. Journal of genetics 1 36814109

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