Affinage

KL

Klotho · UniProt Q9UEF7

Length
1012 aa
Mass
116.2 kDa
Annotated
2026-06-10
100 papers in source corpus 3 papers cited in narrative 4 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Klotho (KL) functions as an aging-suppressor protein whose restoration is sufficient to reverse premature-aging pathology: adenoviral delivery of membrane-form klotho to klotho-deficient mice rescued gonadal atrophy, immune tissue atrophy, and loss of subcutaneous fat while extending lifespan (PMID:10953914). In the kidney, KL expression is repressed during aging through epigenetic silencing, as H3K27me3 accumulates at the KL promoter in aged and KL-mutant kidneys owing to loss of the H3K27 demethylase JMJD3, and PRC2 inhibition reverses this repression to restore KL promoter activity and expression (PMID:32223380). KL deficiency in turn impairs SGK1/FOXO3a signaling and elevates the senescence markers p53 and p16, linking KL to suppression of kidney cell aging (PMID:32223380). Beyond the membrane-form aging-suppressor activity, the related β-klotho co-receptor supports FGF21/FGFR1 signaling in cardiomyocytes, where reinforcing cardiac FGFR1 and β-KL expression alleviates inflammation and endothelial dysfunction under diabetic/metabolic stress (PMID:37123894). The downstream molecular mechanism by which Klotho protein engages the SGK1/FOXO3 axis has not been directly dissected in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2000 Medium

    Established that Klotho protein is causally sufficient, not merely correlated, to reverse premature-aging phenotypes, defining KL as a functional aging suppressor.

    Evidence Adenoviral membrane-form klotho delivery into klotho-deficient (kl/kl) mice with histological and lifespan readouts

    PMID:10953914

    Open questions at the time
    • No molecular mechanism for how Klotho rescues the phenotypes was dissected
    • Multi-organ rescue does not identify a tissue-of-action or direct molecular target
    • Single lab
  2. 2020 Medium

    Answered why KL expression declines with age by identifying PRC2/H3K27me3-mediated epigenetic silencing at the KL promoter as the repressive mechanism.

    Evidence ChIP-qPCR, KL promoter activity assays, PRC2 inhibitor treatment in primary renal tubule cells, aged WT vs KL-mutant kidney comparison

    PMID:32223380

    Open questions at the time
    • Upstream trigger for JMJD3 downregulation during aging is unknown
    • Restricted to renal tubule cells; not shown in other organs
    • Single lab
  3. 2020 Low

    Placed KL upstream of the SGK1/FOXO3a senescence axis, connecting KL deficiency to cellular aging markers in the kidney.

    Evidence Western blot of SGK1/FOXO3a/p53/p16 in aged WT vs KL-mutant kidneys

    PMID:32223380

    Open questions at the time
    • Correlative pathway placement without direct perturbation of SGK1 or FOXO3a
    • Single method (Western blot)
    • No mechanism for how Klotho protein engages SGK1
  4. 2023 Medium

    Defined a distinct β-klotho co-receptor role in cardiomyocyte FGF21/FGFR1 signaling controlling inflammation and angiogenesis under metabolic stress.

    Evidence In vivo mouse diabetic heart models, human diabetic heart tissue, cardiac FGFR1/β-KL overexpression, proteomics

    PMID:37123894

    Open questions at the time
    • This concerns β-klotho (KLB) co-receptor context rather than membrane KL
    • Cardiomyocyte-derived effector factors identified by proteomics are not functionally validated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Klotho protein mechanistically couples to the SGK1/FOXO3 axis and whether the aging-suppressor and FGF co-receptor functions converge remains unresolved.
  • No direct molecular target of secreted/membrane Klotho identified in the corpus
  • No structural or biochemical mechanism for SGK1/FOXO3 regulation
  • Relationship between membrane KL and β-klotho functions not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Pathway
R-HSA-4839726 Chromatin organization 1
Partners
FGFR1

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Adenoviral delivery of the membrane-form klotho gene to klotho-deficient (kl/kl) mice rescued multiple aging-like pathological phenotypes including gonadal atrophy, immune tissue atrophy, and loss of subcutaneous fat, and extended lifespan, establishing that Klotho protein expression is sufficient to reverse these premature-aging phenotypes. Adenoviral gene delivery in vivo; macroscopic and histological analysis of rescued tissues The journal of gene medicine Medium 10953914
2020 H3K27me3 (histone 3 lysine 27 trimethylation) is physically associated with the KL promoter region in renal tubule cells, and its levels increase in aged and KL-mutant mouse kidneys due to downregulation of the H3K27 demethylase JMJD3; inhibition of PRC2 (the H3K27 trimethyltransferase complex) decreased H3K27me3 and increased KL expression and promoter activity, identifying epigenetic silencing via PRC2/H3K27me3 as a mechanism for age-associated KL downregulation. Chromatin immunoprecipitation (ChIP)-qPCR; KL promoter activity assays; Western blot; PRC2 inhibitor treatment in primary renal tubule cells; aged WT and KL-mutant mouse kidney comparison Hypertension (Dallas, Tex. : 1979) Medium 32223380
2020 KL deficiency impairs SGK1 (serum- and glucocorticoid-induced protein kinase 1)/FOXO3a signaling in the kidney, leading to upregulation of p53 and p16 (markers of cellular aging), indicating that Klotho regulates the SGK1/FOXO3 pathway to suppress kidney cell aging. Western blot analysis of SGK1/FOXO3a/p53/p16 in aged WT vs. KL-mutant mouse kidneys Hypertension (Dallas, Tex. : 1979) Low 32223380
2023 In cardiomyocytes under diabetic/metabolic stress, the FGF21/FGFR1–β-klotho (β-KL) signaling cascade is required for anti-inflammatory and proangiogenic responses; decreased FGFR1 and β-KL expression was found in human and mouse diabetic hearts, and reinforcing cardiac FGFR1 and β-KL expression alleviated pro-inflammatory responses and endothelial dysfunction; proteomics identified novel cardiomyocyte-derived factors regulated by FGFR1–β-KL signaling. In vivo mouse diabetic heart models; human diabetic heart tissue analysis; cardiac FGFR1/β-KL overexpression; proteomics Heliyon Medium 37123894

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 1185 1698557
2002 Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. American journal of respiratory and critical care medicine 339 11818324
2012 Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respiratory investigation 316 22554854
1992 Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2. Molecular biology of the cell 287 1378327
1988 Detection of soluble tumor-associated antigens in sera and effusions using novel monoclonal antibodies, KL-3 and KL-6, against lung adenocarcinoma. Japanese journal of clinical oncology 237 3411786
2003 Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. American journal of physiology. Lung cellular and molecular physiology 155 12959931
2006 Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases. Journal of internal medicine 138 17040248
2009 Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. The Journal of rheumatology 136 19286849
2000 Y chromosomal fertility factors kl-2 and kl-3 of Drosophila melanogaster encode dynein heavy chain polypeptides. Proceedings of the National Academy of Sciences of the United States of America 128 11069293
1998 Stage-specific expression of the Kit receptor and its ligand (KL) during male gametogenesis in the mouse: a Kit-KL interaction critical for meiosis. Development (Cambridge, England) 127 9778516
2008 ATRA and KL promote differentiation toward the meiotic program of male germ cells. Cell cycle (Georgetown, Tex.) 102 19098446
2004 Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis. The Journal of rheumatology 102 15170923
2020 Serum KL-6 concentrations as a novel biomarker of severe COVID-19. Journal of medical virology 87 32470148
2010 Prescreening based on the presence of CT-scan abnormalities and biomarkers (KL-6 and SP-D) may reduce severe radiation pneumonitis after stereotactic radiotherapy. Radiation oncology (London, England) 86 20459699
1977 DNA damage in ultraviolet-irradiated HeLa and CHO-Kl cells examined by alkaline lysis and hydroxyapatite chromatography. Biochimica et biophysica acta 82 911843
2011 KL-6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis. Journal of internal medicine 75 21950266
2010 Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients. BMC pulmonary medicine 74 20158912
2011 Surfactant protein D and KL-6 serum levels in systemic sclerosis: correlation with lung and systemic involvement. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG 71 21796888
1998 Serum and bronchoalveolar fluid KL-6 levels in patients with pulmonary alveolar proteinosis. American journal of respiratory and critical care medicine 70 9769294
2003 Study of Clara cell 16, KL-6, and surfactant protein-D in serum as disease markers in pulmonary sarcoidosis. Chest 67 14665489
2015 The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis. Respiratory medicine 66 26481343
2018 MUC1 aptamer-targeted DNA micelles for dual tumor therapy using doxorubicin and KLA peptide. Nanomedicine : nanotechnology, biology, and medicine 60 29317345
2000 Serum KL-6 in adult patients with polymyositis and dermatomyositis. Rheumatology (Oxford, England) 60 10888708
2021 Serum KL-6, CA19-9, CA125 and CEA are Diagnostic Biomarkers for Rheumatoid Arthritis-Associated Interstitial Lung Disease in the Chinese Population. Rheumatology and therapy 58 33586127
2012 Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels. Respiratory medicine 58 22995277
2017 Serum KL-6 and surfactant protein-D as monitoring and predictive markers of interstitial lung disease in patients with systemic sclerosis and mixed connective tissue disease. Journal of thoracic disease 55 28275485
2023 Auto-Kla: a novel web server to discriminate lysine lactylation sites using automated machine learning. Briefings in bioinformatics 54 36869843
1993 The kl-3 loop of the Y chromosome of Drosophila melanogaster binds a tektin-like protein. Genetics 54 8454204
2009 Differential cytokine/chemokines and KL-6 profiles in patients with different forms of tuberculosis. Cytokine 53 19570688
2000 Improvement of multiple pathophysiological phenotypes of klotho (kl/kl) mice by adenovirus-mediated expression of the klotho gene. The journal of gene medicine 50 10953914
2005 Serum KL-6 and surfactant proteins A and D in pediatric interstitial lung disease. Chest 49 15654008
2021 KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease. Nature communications 45 34158479
2015 Enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA on human brain metastatic breast cancer. Scientific reports 43 25619721
2010 Association of the functional KL-VS variant of Klotho gene with early-onset ischemic stroke. Biochemical and biophysical research communications 42 21093413
2008 Serum surfactant protein-A, but not surfactant protein-D or KL-6, can predict preclinical lung damage induced by smoking. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 40 18595202
2023 Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma. Scientific reports 38 37903971
2019 Serum neopterin as well as ferritin, soluble interleukin-2 receptor, KL-6 and anti-MDA5 antibody titer provide markers of the response to therapy in patients with interstitial lung disease complicating anti-MDA5 antibody-positive dermatomyositis. Modern rheumatology 38 30449228
2020 Epigenetic Regulation of KL (Klotho) via H3K27me3 (Histone 3 Lysine [K] 27 Trimethylation) in Renal Tubule Cells. Hypertension (Dallas, Tex. : 1979) 37 32223380
2023 Lysine lactylation (Kla) might be a novel therapeutic target for breast cancer. BMC medical genomics 36 37950222
2009 Potential-dependent membrane permeabilization and mitochondrial aggregation caused by anticancer polyarginine-KLA peptides. Archives of biochemistry and biophysics 35 19900399
2009 Clinicopathology of sialomucin: MUC1, particularly KL-6 mucin, in gastrointestinal, hepatic and pancreatic cancers. Bioscience trends 35 20103851
2020 Lung ultrasound B-lines and serum KL-6 correlate with the severity of idiopathic inflammatory myositis-associated interstitial lung disease. Rheumatology (Oxford, England) 33 31794028
2018 Synergistic effect of the pro-apoptosis peptide kla-TAT and the cationic anticancer peptide HPRP-A1. Apoptosis : an international journal on programmed cell death 32 29397453
2001 The paralemmin protein family: identification of paralemmin-2, an isoform differentially spliced to AKAP2/AKAP-KL, and of palmdelphin, a more distant cytosolic relative. Biochemical and biophysical research communications 31 11478809
2020 Serum KL-6 levels in pulmonary Langerhans' cell histiocytosis. European journal of clinical investigation 30 32307698
2013 Correlation between mass transfer coefficient kLa and relevant operating parameters in cylindrical disposable shaken bioreactors on a bench-to-pilot scale. Journal of biological engineering 30 24289110
2011 Ageing and long-term smoking affects KL-6 levels in the lung, induced sputum and plasma. BMC pulmonary medicine 30 21569324
2007 Immunohistochemical and immunoelectron microscopic studies of the localization of KL-6 and epithelial membrane antigen (EMA) in presumably normal pulmonary tissue and in interstitial pneumonia. Medical molecular morphology 30 18085378
2011 Levels of surfactant proteins A and D and KL-6 are elevated in the induced sputum of chronic obstructive pulmonary disease patients: a sequential sputum analysis. Respiration; international review of thoracic diseases 29 21474912
2005 Studies on the cellular uptake of substance P and lysine-rich, KLA-derived model peptides. Journal of molecular recognition : JMR 29 15386618
2021 Serum KL-6 Could Represent a Reliable Indicator of Unfavourable Outcome in Patients with COVID-19 Pneumonia. International journal of environmental research and public health 28 33672761
2016 MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis. Orphanet journal of rare diseases 28 27108412
2012 The elevation of serum napsin A in idiopathic pulmonary fibrosis, compared with KL-6, surfactant protein-A and surfactant protein-D. BMC pulmonary medicine 28 22963039
2018 Diagnostic value of KL-6 in idiopathic interstitial pneumonia. Journal of thoracic disease 27 30233844
2020 Bronchoalveolar lavage and serum KL-6 concentrations in chronic hypersensitivity pneumonitis: correlations with radiological and immunological features. Internal and emergency medicine 26 32078140
2005 KL-6 and surfactant proteins A and D in serum and bronchoalveolar lavage fluid in patients with acute eosinophilic pneumonia. Internal medicine (Tokyo, Japan) 26 16157978
2001 KL-6, surfactant protein A and D in bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis. Respiration; international review of thoracic diseases 26 11694811
2022 Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study. The Lancet regional health. Western Pacific 25 36879786
2011 Pneumocyte biomarkers KL-6 and surfactant protein D reflect the distinct findings of high-resolution computed tomography in nonspecific interstitial pneumonia. Respiration; international review of thoracic diseases 25 21555868
2022 Association of Klotho Protein Levels and KL-VS Heterozygosity With Alzheimer Disease and Amyloid and Tau Burden. JAMA network open 24 36413367
2002 KL/KIT co-expression in mouse fetal oocytes. The International journal of developmental biology 24 12533025
2020 Serum SP-A and KL-6 levels can predict the improvement and deterioration of patients with interstitial pneumonia with autoimmune features. BMC pulmonary medicine 23 33267857
2021 Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes. Journal of Alzheimer's disease : JAD 22 33427737
2019 Coadministration of kla peptide with HPRP-A1 to enhance anticancer activity. PloS one 20 31703065
2016 [The expression and clinical role of KL-6 in serum and BALF of patients with different diffuse interstitial lung diseases]. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 20 26879611
2022 YKL-40 and KL-6 Levels in Serum and Sputum of Patients Diagnosed With Hypersensitivity Pneumonitis. The journal of allergy and clinical immunology. In practice 19 35788062
2014 A comparison of KL-6 and Clara cell protein as markers for predicting bronchopulmonary dysplasia in preterm infants. Disease markers 19 25242856
2021 Association of serum KL-6 levels on COVID-19 severity: A cross-sectional study design with purposive sampling. Annals of medicine and surgery (2012) 17 34401147
2012 Phenethyl caffeate benzo[kl]xanthene lignan with DNA interacting properties induces DNA damage and apoptosis in colon cancer cells. Life sciences 17 23123449
2009 Serum KL-6 as a novel disease marker in adolescent and adult cystic fibrosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG 17 19960788
2008 Drosophila melanogaster kl-3 and kl-5 Y-loops harbor triple-stranded nucleic acids. Journal of cell science 17 18430782
2018 Anti-KL-6/MUC1 monoclonal antibody reverses resistance to trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity by capping MUC1. Cancer letters 16 30389434
2017 The KL-VS polymorphism of KLOTHO gene is protective against retinopathy incidence in patients with type 1 diabetes. Biochimica et biophysica acta. Molecular basis of disease 16 29247834
2006 Anti-tumor effect of the anti-KL-6/MUC1 monoclonal antibody through exposure of surface molecules by MUC1 capping. Cancer science 16 16630141
2003 KL-6, a human MUC1 mucin, is expressed early in premature lung. Respiratory medicine 16 12924525
2023 FGF21/FGFR1-β-KL cascade in cardiomyocytes modulates angiogenesis and inflammation under metabolic stress. Heliyon 15 37123894
2021 The value of KL-6 in the diagnosis and assessment of interstitial lung disease. American journal of translational research 15 34540037
2013 Bleomycin-induced pulmonary fibrosis is attenuated by an antibody against KL-6. Experimental lung research 15 23672275
2013 KL-6 regulated the expression of HGF, collagen and myofibroblast differentiation. European review for medical and pharmacological sciences 15 24302189
2024 KL-Biome (Postbiotic Formulation of Lactiplantibacillus plantarum KM2) Improves Dexamethasone-Induced Muscle Atrophy in Mice. International journal of molecular sciences 14 39000606
2024 KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults. Alzheimer's & dementia : the journal of the Alzheimer's Association 14 39030746
2020 Krebs von den Lungen-6 (KL-6) is a pathophysiological biomarker of early-stage acute hypersensitivity pneumonitis among pigeon fanciers. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 14 32966647
2017 Specific hepatic stellate cell-penetrating peptide targeted delivery of a KLA peptide reduces collagen accumulation by inducing apoptosis. Journal of drug targeting 14 28447897
2011 Klotho KL-VS genotype is involved in blood pressure regulation. Clinica chimica acta; international journal of clinical chemistry 14 21663735
2009 Partitioning, dynamics, and orientation of lung surfactant peptide KL(4) in phospholipid bilayers. Biochimica et biophysica acta 14 19735643
2006 Simultaneous measurements of KL-6 and SP-D in patients undergoing thoracic radiotherapy. Medical oncology (Northwood, London, England) 14 16645232
2023 KL-6 levels in the connective tissue disease population: typical values and potential confounders-a retrospective, real-world study. Frontiers in immunology 13 37409133
2017 Anti-inflammatory activities and glycerophospholipids metabolism in KLA-stimulated RAW 264.7 macrophage cells by diarylheptanoids from the rhizomes of Alpinia officinarum. Biomedical chromatography : BMC 13 28906002
2011 Expression of KL-6/MUC1 in pancreatic cancer tissues and its potential involvement in tumor metastasis. Oncology reports 13 21617869
2009 Expression of KL-6 mucin, a human MUC1 mucin, in intrahepatic cholangiocarcinoma and its potential involvement in tumor cell adhesion and invasion. Life sciences 13 19631667
1988 Immunohistochemistry (S 100, KL 1) and human papillomavirus DNA hybridization on morbus Bowen and bowenoid papulosis. Virchows Archiv. A, Pathological anatomy and histopathology 13 2455378
2014 Inhibition of KL-6/MUC1 glycosylation limits aggressive progression of pancreatic cancer. World journal of gastroenterology 12 25232251
2013 A novel lung injury animal model using KL-6-measurable human MUC1-expressing mice. Biochemical and biophysical research communications 12 23410752
2024 Research progress of KL-6 in respiratory system diseases. Critical reviews in clinical laboratory sciences 11 38773736
2022 AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes. Alzheimer's & dementia (Amsterdam, Netherlands) 11 36505396
2017 Impact of anti-tumor necrosis factor-α agents on serum levels of KL-6 and surfactant protein-D in patients with psoriasis. The Journal of dermatology 11 28370220
2011 Expression of KL-6/MUC1 in pancreatic ductal carcinoma and its potential relationship with β-catenin in tumor progression. Life sciences 11 21466814
2001 Domain and genomic sequence analysis of bdellin-KL, a leech-derived trypsin-plasmin inhibitor. Journal of biochemistry 11 11530020
2025 Serum KL-6 and SP-D: Markers of Lung Function in Autoimmune-Related Interstitial Lung Diseases. International journal of molecular sciences 10 39940859
2024 Histone Lysine Lactylation (Kla)-induced BCAM Promotes OSCC Progression and Cis-Platinum Resistance. Oral diseases 10 39503345

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