Affinage

CLTRN

Collectrin · UniProt Q9HBJ8

Length
222 aa
Mass
25.2 kDa
Annotated
2026-06-09
15 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLTRN/collectrin (TMEM27) is a type I transmembrane glycoprotein that couples epithelial amino acid handling and pancreatic beta cell physiology to membrane-anchored signaling and regulated proteolysis (PMID:16330324, PMID:31520464). In the renal proximal tubule brush-border epithelium it acts as a chaperone required for trafficking and activation of the neutral amino acid transporter B0AT1, and human loss-of-function produces a neutral aminoaciduria resembling Hartnup disease (PMID:31520464). Independently in the proximal tubule, collectrin regulates blood pressure homeostasis, with its deletion raising baseline NHE3 expression and reducing lithium excretion (PMID:36264884). In pancreatic beta cells, the membrane-anchored full-length protein drives proliferation and enhances glucose-stimulated insulin secretion, whereas truncated or shed soluble forms do not (PMID:16330324, PMID:20386877). Collectrin forms homodimers through an intracellular cysteine, and this dimerization protects it from BACE2-mediated cleavage; N-glycosylation of an extracellular asparagine is required for plasma-membrane trafficking and subsequent BACE2 processing, and a Phe-Phe motif at the cleavage site acts as an intramolecular BACE2 inhibitor (PMID:22628310). CLTRN expression is transcriptionally controlled, being induced by NRF1 and repressed by G9a-mediated H3K9me2 at its promoter, and its upregulation activates glutathione metabolism and promotes ferroptosis, thereby enhancing radiosensitivity in tumor cells (PMID:33508374, PMID:41213903).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2005 High

    Established that membrane-anchored, not soluble, collectrin is the functional species driving beta cell proliferation, defining the protein's form-function relationship.

    Evidence Dimerization/glycosylation/cleavage biochemistry plus overexpression, RNAi, and beta cell-specific transgenic mouse

    PMID:16330324

    Open questions at the time
    • Downstream proliferative signaling effectors not identified
    • Identity of the cleaving protease not yet established in this study
  2. 2010 Medium

    Extended beta cell function to glucose-stimulated insulin secretion and showed cleavage/shedding is not beta cell-specific, refining its candidacy as a tissue-specific biomarker.

    Evidence Overexpression in beta cell line and islets with insulin secretion assay; comparative cleavage in renal proximal tubular cells

    PMID:20386877

    Open questions at the time
    • Mechanism linking collectrin to the secretory machinery not defined
    • Single lab
  3. 2012 High

    Resolved the molecular control of collectrin processing, showing dimerization, glycosylation, and an intramolecular motif jointly gate BACE2 cleavage.

    Evidence Cysteine/asparagine/Phe-Phe mutational analysis with dimerization, trafficking, and BACE2 cleavage assays

    PMID:22628310

    Open questions at the time
    • Physiological trigger that shifts dimer-to-monomer equilibrium in vivo unclear
    • Functional consequence of shed ectodomain unresolved
  4. 2014 Medium

    Identified an upstream regulator of collectrin protein abundance, linking active vitamin D to its expression in beta cells.

    Evidence SILAC quantitative proteomics in INS-1 cells treated with 1,25-(OH)2D3

    PMID:24693993

    Open questions at the time
    • Transcriptional vs post-transcriptional basis of upregulation not dissected
    • Single method, single lab
  5. 2019 Medium

    Defined collectrin's renal chaperone role for B0AT1 and tied human loss-of-function to a defined aminoaciduria phenotype.

    Evidence Human loss-of-function (exon deletion) with urinary amino acid analysis; mouse brain expression mapping

    PMID:31520464

    Open questions at the time
    • Functional role of abundant brain expression uncharacterized
    • Single family/lab
  6. 2022 High

    Established a distinct proximal-tubule role in blood pressure regulation acting at least partly through NHE3.

    Evidence Proximal tubule-specific conditional knockout mouse with blood pressure, NHE3 expression, and lithium excretion readouts

    PMID:36264884

    Open questions at the time
    • Direct vs indirect mechanism of NHE3 upregulation not resolved
    • Relationship to its B0AT1 chaperone role unclear
  7. 2021 Medium

    Connected CLTRN to ferroptosis and radiosensitivity, identifying transcriptional and protein-interaction context for this role.

    Evidence RNA-seq, glutathione/iron/ROS assays, TEM, NRF1 binding assay, and co-IP for DLD and RAN; in vitro and in vivo in hepatocellular carcinoma

    PMID:33508374

    Open questions at the time
    • Mechanistic link between CLTRN and glutathione pathway activation not defined
    • Functional significance of DLD/RAN interactions untested
  8. 2025 Medium

    Identified epigenetic repression of TMEM27 by G9a as a controllable node governing ferroptosis-dependent radiosensitivity.

    Evidence ChIP-qPCR for G9a/H3K9me2 at TMEM27 promoter, G9a knockout and BRD4770 inhibition, RNA-seq, ferroptosis assays in head and neck squamous cell carcinoma

    PMID:41213903

    Open questions at the time
    • How de-repressed TMEM27 mechanistically drives ferroptosis not resolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How collectrin's distinct roles (B0AT1 chaperone, NHE3-linked blood pressure control, beta cell proliferation/secretion, and ferroptosis promotion) are mechanistically unified or independently wired remains unresolved.
  • No structural model of collectrin in complex with B0AT1 or BACE2
  • Effectors downstream of membrane-anchored collectrin in beta cells unidentified
  • Mechanism connecting CLTRN to glutathione metabolism/ferroptosis undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0044183 protein folding chaperone 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-382551 Transport of small molecules 2 R-HSA-5357801 Programmed Cell Death 2
Partners
BACE2DLDNHE3RANSLC6A19

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Tmem27 (collectrin) forms homodimers and its extracellular domain is glycosylated, cleaved, and shed from the plasma membrane of pancreatic beta cells. This cleavage is beta cell-specific. Overexpression of full-length Tmem27 (but not truncated or soluble forms) increases thymidine incorporation, while RNAi silencing reduces cell replication, establishing that membrane-anchored Tmem27 drives beta cell proliferation. Biochemical characterization (dimerization, glycosylation, cleavage assays), overexpression and RNAi knockdown in beta cells, transgenic mouse model with beta cell-specific overexpression Cell metabolism High 16330324
2010 TMEM27 overproduction in a beta cell line and isolated islets significantly enhances glucose-induced insulin secretion. Its cleavage and shedding occurs in both renal proximal tubular cells and pancreatic islets, showing the cleavage is not beta cell-specific, which challenges its use as a beta cell-specific biomarker. Overexpression in beta cell line and primary islets (insulin secretion assay); cleavage assay in renal proximal tubular cells and islets Diabetologia Medium 20386877
2012 Tmem27 dimerization via its intracellular cysteine residue is a dynamic process that prevents its cleavage by Bace2. Extracellular asparagine glycosylation is essential for Tmem27 trafficking to the plasma membrane and subsequent processing by Bace2. The amount of Tmem27 at the plasma membrane is proportional to total cell levels upon glucose stimulation and Bace2 inhibition. The double phenylalanine (Phe-Phe) motif in the Tmem27 cleavage site functions as an intramolecular Bace2 inhibitor. Tmem27 mutational analysis (cysteine and asparagine mutants, Phe-Phe motif mutants), biochemical assays (dimerization, glycosylation, trafficking, cleavage), Bace2 inhibition experiments Biological chemistry High 22628310
2019 Collectrin (CLTRN) functions as a chaperone required for the transport and activation of the neutral amino acid transporter B0AT1 in the renal apical brush border epithelium; loss-of-function in humans causes neutral aminoaciduria mimicking Hartnup disease. Collectrin expression was found to be particularly abundant in mouse hippocampus, brainstem, and cerebellum. Human loss-of-function (hemizygous deletion, exon 1-3 deletion), urinary amino acid analysis; mouse brain expression analysis by immunostaining/fractionation American journal of medical genetics. Part A Medium 31520464
2022 Proximal tubule-specific deletion of collectrin (Tmem27) in mice causes hypertension associated with increased baseline NHE3 (Na+/H+ exchanger isoform 3) expression and diminished lithium excretion, demonstrating that collectrin in proximal tubules regulates blood pressure homeostasis at least partly through NHE3 activity. Conditional (proximal tubule-specific) knockout mouse model; blood pressure measurement, NHE3 protein expression, lithium excretion assay, endothelial dilation assay American journal of physiology. Renal physiology High 36264884
2021 CLTRN overexpression activates the glutathione metabolic pathway and promotes ferroptosis (iron-dependent, lipid peroxidation-driven cell death), thereby enhancing radiosensitivity in hepatocellular carcinoma cells. NRF1 was identified as an upstream transcription factor of CLTRN, and DLD (dihydrolipoamide dehydrogenase) and RAN (a RAS oncogene family member) were identified as CLTRN-interacting proteins. RNA-seq after CLTRN overexpression, glutathione pathway analysis, cellular iron measurement, ROS assay, transmission electron microscopy, ferroptosis marker detection, transcription factor binding assay, co-immunoprecipitation for interacting proteins; in vitro and in vivo experiments International journal of radiation oncology, biology, physics Medium 33508374
2025 G9a (a histone H3K9 methyltransferase) binds the H3K9me2 site of the TMEM27 promoter and represses TMEM27 transcription; G9a deficiency or inhibition de-represses TMEM27, promoting ferroptosis and enhancing radiosensitivity in head and neck squamous cell carcinoma cells. This regulation depends on G9a's histone methyltransferase activity. ChIP-qPCR (G9a binding to TMEM27 H3K9me2 locus), G9a knockout and small-molecule inhibition (BRD4770), RNA sequencing, KEGG pathway analysis, ferroptosis assays Cell death discovery Medium 41213903
2014 Tmem27 protein in INS-1 beta cells is upregulated (up to sevenfold) at the protein level by treatment with 1,25-(OH)2D3 (active vitamin D metabolite), as identified by SILAC-based quantitative proteomics. SILAC quantitative proteomics (LC-MS) in INS-1 cells treated with 1,25-(OH)2D3 Scandinavian journal of clinical and laboratory investigation Medium 24693993

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Tmem27: a cleaved and shed plasma membrane protein that stimulates pancreatic beta cell proliferation. Cell metabolism 114 16330324
2021 CLTRN, Regulated by NRF1/RAN/DLD Protein Complex, Enhances Radiation Sensitivity of Hepatocellular Carcinoma Cells Through Ferroptosis Pathway. International journal of radiation oncology, biology, physics 40 33508374
2010 The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker. Diabetologia 29 20386877
2009 Locus heterogeneity of Dent's disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations. Pediatric nephrology (Berlin, Germany) 26 19582483
2012 Multimodal imaging of pancreatic beta cells in vivo by targeting transmembrane protein 27 (TMEM27). Diabetologia 18 22790173
2012 Tmem27 dimerization, deglycosylation, plasma membrane depletion, and the extracellular Phe-Phe motif are negative regulators of cleavage by Bace2. Biological chemistry 15 22628310
2019 Loss of CLTRN function produces a neuropsychiatric disorder and a biochemical phenotype that mimics Hartnup disease. American journal of medical genetics. Part A 11 31520464
2014 Automated assessment of β-cell area and density per islet and patient using TMEM27 and BACE2 immunofluorescence staining in human pancreatic β-cells. PloS one 11 24905913
2014 Tmem27 is upregulated by vitamin D in INS-1 cells and its serum concentrations are low in patients with autoimmune diabetes. Scandinavian journal of clinical and laboratory investigation 8 24693993
2022 Collectrin (Tmem27) deficiency in proximal tubules causes hypertension in mice and a TMEM27 variant associates with blood pressure in males in a Latino cohort. American journal of physiology. Renal physiology 7 36264884
2007 Collectrin/tmem27 is expressed at high levels in all segments of the developing Xenopus pronephric nephron and in the Wolffian duct. Gene expression patterns : GEP 7 18226983
2022 Urinary Collectrin (TMEM27) as Novel Marker for Acute Kidney Injury. Life (Basel, Switzerland) 6 36143426
2016 Lack of TMEM27 expression is associated with postoperative progression of clinically localized conventional renal cell carcinoma. Journal of cancer research and clinical oncology 5 27417314
2025 G9a deficiency activates TMEM27 to promote ferroptosis and enhances radiosensitivity in head and neck squamous cell carcinoma. Cell death discovery 2 41213903
2022 TMEM27 expression and clinical characteristics and survival in clear cell renal cell carcinoma. Acta oncologica (Stockholm, Sweden) 2 36369873

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