Affinage

ILDR1

Immunoglobulin-like domain-containing receptor 1 · UniProt Q86SU0

Length
546 aa
Mass
62.8 kDa
Annotated
2026-04-28
23 papers in source corpus 12 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ILDR1 (angulin-2) is a tricellular tight junction (tTJ) membrane protein that maintains paracellular barrier integrity by recruiting tricellulin to tricellular contacts through its extracellular Ig-like domain, which also mediates homo-trimerization (PMID:23239027, PMID:25668204). In the kidney, ILDR1 controls paracellular water impermeability in distal tubules, and its loss causes polyuria from renal concentrating defects without altering ionic permeability (PMID:28461473). ILDR1 is required for cochlear hair cell survival: knockout mice exhibit progressive outer hair cell degeneration and profound deafness—a phenotype rescued by dual-AAV gene replacement—establishing ILDR1 loss-of-function as the basis of DFNB42 autosomal recessive deafness (PMID:25217574, PMID:37481704). Beyond its junctional role, ILDR1 binds nuclear splicing factors TRA2A, TRA2B, and SRSF1 and regulates alternative pre-mRNA splicing of targets including TUBD1 and IQCB1 (PMID:28785060).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2012 High

    The molecular function of ILDR1 at cell junctions was unknown; demonstration that ILDR1 localizes to tricellular tight junctions and recruits tricellulin established it as a core tTJ organizer, directly linking DFNB42 mutations to defective tricellulin recruitment.

    Evidence Immunofluorescence and expression of DFNB42-associated mutant ILDR1 in cultured epithelial cells with barrier assays

    PMID:23239027

    Open questions at the time
    • Structural basis of ILDR1–tricellulin interaction unresolved
    • In vivo confirmation of tTJ role pending
    • Whether ILDR1 functions beyond the inner ear unknown
  2. 2014 High

    Whether ILDR1 loss disrupts tTJ ultrastructure in vivo was unknown; freeze-fracture EM and knockout mouse analysis demonstrated disrupted tTJ strands in the inner ear, postnatal hair cell degeneration, and tricellulin mislocalization, confirming ILDR1 as essential for tTJ integrity and cochlear survival.

    Evidence Ildr1 knockout mouse, freeze-fracture EM, ABR, immunofluorescence; zebrafish morpholino knockdown with epistasis analysis

    PMID:24990150 PMID:25217574

    Open questions at the time
    • Mechanism of hair cell death (apoptotic vs necrotic) uncharacterized
    • Zebrafish FGF/Na+K+-ATPase pathway link not confirmed in mammals
    • Compensatory mechanisms by other angulins not quantified
  3. 2015 Medium

    Whether other angulin family members compensate for ILDR1 loss was unclear; independent knockout studies showed LSR/angulin-1 is upregulated at tTJs in ILDR1-null cochleae, and structure–function analysis indicated the Ig-like domain mediates homo-trimerization required for tTJ assembly.

    Evidence Two independent Ildr1 knockout mouse studies with immunofluorescence; expression of ILDR1 variants in LSR-knockdown epithelial cells with 3D modeling

    PMID:25668204 PMID:25819842 PMID:25822906

    Open questions at the time
    • Homo-trimer model based on computational prediction, not experimentally validated
    • Whether LSR compensation fully rescues barrier in non-cochlear tissues untested
  4. 2017 High

    ILDR1's physiological role outside the ear was unknown; kidney microperfusion experiments revealed that ILDR1 selectively controls paracellular water permeability in distal tubules, and independently, ILDR1 was shown to bind splicing factors TRA2A/TRA2B/SRSF1 and regulate alternative splicing, revealing a second, nuclear function.

    Evidence Knockout mouse with live tubule microperfusion and gain-of-function in renal cells; Co-IP, yeast two-hybrid, nuclear translocation, and RT-PCR splice assays

    PMID:28461473 PMID:28785060

    Open questions at the time
    • How a membrane tTJ protein accesses nuclear splicing machinery is mechanistically unclear
    • Splicing targets relevant to hearing or kidney phenotypes not identified
    • Single-lab evidence for splicing function
  5. 2020 Medium

    Whether ILDR1 loss affects intestinal barrier was untested; Ussing chamber analysis showed no detectable paracellular water transport change in colon, explained by compensatory LSR redistribution to tricellular contacts.

    Evidence Ildr1 knockout mouse, Ussing chamber electrophysiology, immunofluorescence of colon and kidney

    PMID:32587380

    Open questions at the time
    • Whether compensation is complete or partial in all intestinal segments unclear
    • Mechanism driving LSR redistribution unknown
  6. 2022 Medium

    ILDR1's roles beyond barrier function were expanded: it modulates metabolic and satiety responses via expression in enteroendocrine and pancreatic islet cells, and separately interacts with PLSCR1 to influence antiviral signaling.

    Evidence Ildr1 knockout mouse with metabolic phenotyping (CLAMS, OGTT, islet perifusion); yeast two-hybrid and Co-IP for PLSCR1 interaction with knockout infection model

    PMID:35595813 PMID:35749484

    Open questions at the time
    • Whether metabolic phenotype is secondary to tTJ dysfunction or a direct signaling role is unresolved
    • PLSCR1 interaction relevance to physiological ILDR1 function unclear
    • Both findings from single labs
  7. 2023 Medium

    Whether gene replacement could rescue ILDR1-dependent deafness was unknown; dual-AAV delivery of Ildr1 to both organ of Corti and cochlear lateral wall improved auditory function and cochlear structure, establishing that ILDR1 is required in multiple cochlear compartments.

    Evidence AAV2.7m8 + AAV8BP2 gene therapy in Ildr1 knockout mouse, ABR, cochlear histology

    PMID:37481704

    Open questions at the time
    • Long-term durability of rescue not established
    • Whether single-vector strategies could suffice untested
    • Lateral wall cell type requiring ILDR1 not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of ILDR1 homo-trimerization and tricellulin recruitment, the mechanism by which a membrane-bound tTJ protein translocates to the nucleus to regulate splicing, and whether the metabolic phenotype reflects a direct signaling role or secondary barrier defects remain unresolved.
  • No crystal or cryo-EM structure of ILDR1 or ILDR1–tricellulin complex
  • Nuclear translocation mechanism uncharacterized
  • Causal relationship between tTJ defects and metabolic/satiety phenotype not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 1
Pathway
R-HSA-1500931 Cell-Cell communication 4 R-HSA-382551 Transport of small molecules 1 R-HSA-8953854 Metabolism of RNA 1
Partners
LSRPLSCR1SRSF1TRA2ATRA2BTRIC

Evidence

Reading pass · 13 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 and recruits tricellulin to these junctions; DFNB42-associated ILDR1 mutant proteins are defective in tricellulin recruitment, and tricellulin DFNB49 mutant proteins fail to be recruited to tTJs by ILDR1. Immunofluorescence localization, expression of ILDR1 mutant proteins in cultured epithelial cells, functional barrier assays Journal of cell science High 23239027
2012 ILDR1 is required for the establishment of a strong epithelial barrier when introduced into cultured epithelial cells, as assessed by transepithelial resistance measurements. Overexpression in cultured epithelial cells with transepithelial resistance measurement Journal of cell science High 23239027
2014 In ILDR1 null mice, tricellular tight junction ultrastructure in the inner ear is disrupted (shown by freeze-fracture electron microscopy), cochlear hair cells degenerate postnatally, and tricellulin becomes mislocalized after the first postnatal week, while the endocochlear potential remains normal. Knockout mouse model, freeze-fracture electron microscopy, ABR hearing tests, immunofluorescence Human molecular genetics High 25217574
2015 In Ildr1 null mice, cochlear hair cells develop normally but undergo postnatal degeneration; tricellulin localization at tricellular contacts is retained but its distribution along the depth of tricellular contacts is altered. Compensatory upregulation of angulin-1/LSR at organ of Corti tricellular contacts occurs in the absence of ILDR1. Targeted gene disruption (knockout mouse), immunofluorescence, ABR hearing tests PloS one High 25822906
2015 ILDR1 deficiency preferentially causes degeneration of outer hair cells and disrupts tunnel formation in the organ of Corti; ILDR1 deficiency affects tricellulin expression in vivo. Knockout mouse model, histology, confocal microscopy, differential proteomics Biology open Medium 25819842
2015 The ILDR1 p.P69H variant (in the Ig-like domain) causes partial mislocalization of ILDR1 and tricellulin at tricellular contacts, while other DFNB42 ILDR1 mutations cause complete failure of tricellulin recruitment; 3D modeling predicts ILDR1 forms homo-trimers through its Ig-like domain required for tTJ assembly. Expression of ILDR1 variants in angulin-1/LSR knockdown epithelial cells, immunofluorescence, 3D protein modeling PloS one Medium 25668204
2017 ILDR1 regulates paracellular water transport at tricellular tight junctions in kidney distal tubules; Ildr1 knockout mice develop polyuria and polydipsia due to renal concentrating defects, and knockout distal tubules become highly permeable to water without affecting paracellular ionic permeability; overexpression of Ildr1 in renal epithelial cells reduces paracellular water permeability. Knockout mouse model, live tubule microperfusion, osmotic water permeability measurements, overexpression in cultured renal epithelial cells Proceedings of the National Academy of Sciences of the United States of America High 28461473
2017 ILDR1 binds to pre-mRNA splicing factors TRA2A, TRA2B, and SRSF1, translocates to the nucleus when these splicing factors are present, and regulates alternative splicing of TUBD1, IQCB1, and PCDH19; siRNA knockdown of endogenous ILDR1 and ILDR2 affects alternative splicing of TUBD1 and IQCB1. Co-immunoprecipitation, yeast two-hybrid, nuclear translocation assay, RT-PCR splice assays, siRNA knockdown Scientific reports Medium 28785060
2014 In ildr1b-morphant zebrafish, semicircular canal development is defective, lateral line primordium migration is impaired due to disrupted FGF signaling and reduced cxcr4b/cxcr7b expression; injection of atp1b2b mRNA rescues the semicircular canal developmental delay, placing ILDR1 upstream of Na+/K+ ATPase beta-2b in inner ear development. Morpholino knockdown in zebrafish, in situ hybridization, mRNA rescue, gene expression profiling Human molecular genetics Medium 24990150
2022 ILDR1 binds to PLSCR1 (phospholipid scramblase 1) competitively, preventing PLSCR1 from interacting with influenza A virus NP protein, thereby promoting viral replication; this defines an ILDR1-PLSCR1-NP regulatory pathway. Yeast two-hybrid screening, co-immunoprecipitation, Plscr1 knockout mouse infection model Scientific reports Medium 35595813
2022 ILDR1 is expressed in cholecystokinin-positive enteroendocrine cells and in pancreatic alpha and beta cells; Ildr1 deletion in mice leads to increased food intake but reduced weight gain on high-fat diet, improved glucose tolerance, enhanced insulin sensitivity, and increased glucose-regulated insulin secretion, indicating ILDR1 modulates metabolic and satiety responses. Knockout mouse model, CLAMS metabolic chambers, targeted metabolomics, ELISA, oral glucose tolerance test, ex vivo islet perifusion, confocal microscopy PloS one Medium 35749484
2020 Ildr1 knockout mice show no detectable change in large intestinal paracellular water transport; however, angulin-1/LSR redistributes to tricellular contacts in the colon and kidney of Ildr1 knockout mice, indicating compensatory replacement of ILDR1 by LSR in these tissues. Knockout mouse model, Ussing chamber electrophysiology, immunofluorescence Scientific reports Medium 32587380
2023 Combined delivery of two AAVs (AAV2.7m8 targeting organ of Corti; AAV8BP2 targeting cochlear lateral wall) carrying Ildr1 cDNA improves cochlear structural integrity and auditory function in Ildr1w-/- mice, demonstrating that ILDR1 function is required in both the organ of Corti and the cochlear lateral wall for normal hearing. AAV-mediated gene therapy in knockout mouse, ABR hearing measurements, cochlear histology Molecular therapy Medium 37481704

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 88 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 71 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