Affinage

CTSG

Cathepsin G · UniProt P08311

Length
255 aa
Mass
28.8 kDa
Annotated
2026-06-09
100 papers in source corpus 3 papers cited in narrative 3 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

Cathepsin G (CTSG) is a myeloid serine protease whose proteolytic activity has been linked to chromatin remodeling during monocyte differentiation and to tumor-suppressive signaling (PMID:34017121, PMID:37151875). Together with neutrophil elastase (ELANE) and proteinase 3 (PRTN3), CTSG cleaves the histone H3 amino terminus (H3ΔN) in primary human monocytes; this mark is abundant in monocytes and lost upon macrophage differentiation, and simultaneous depletion of the three proteases abolishes H3ΔN and increases chromatin accessibility, implicating CTSG-mediated H3 cleavage as an epigenetic priming mechanism in the monocyte-to-macrophage transition (PMID:34017121). CTSG expression is not confined to mature myeloid cells: its regulatory elements are active in hematopoietic stem/progenitor cells, and endogenous Ctsg is functionally expressed across early myeloid progenitors (PMID:23056333). In colorectal cancer, CTSG acts as a tumor suppressor, restraining proliferation and tumor growth by suppressing the Akt/mTOR/Bcl2 anti-apoptotic axis, with Akt inhibition epistatically abolishing the pro-survival effects of CTSG loss (PMID:37151875).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2012 Medium

    Defining where in the hematopoietic hierarchy CTSG is expressed established that it is active not only in promyelocytes but in multipotent progenitors, refining its expression domain and the cellular context of its activity.

    Evidence Ctsg-PML-RARA transgenic knockin mice, FACS-sorted HSPC/progenitor analysis, competitive repopulation and progenitor transcriptome profiling

    PMID:23056333

    Open questions at the time
    • Does not characterize a proteolytic substrate or molecular function of CTSG in progenitors
    • Effects observed via PML-RARA expression driven by CTSG elements, not via CTSG protein activity itself
  2. 2021 High

    Identification of histone H3 N-terminal cleavage (H3ΔN) as a CTSG/ELANE/PRTN3-catalyzed mark answered whether these proteases have a nuclear, chromatin-directed role, establishing CTSG as an epigenetic effector that primes chromatin during monocyte-to-macrophage differentiation.

    Evidence Integrative epigenomics, simultaneous NSP depletion (loss-of-function), and chromatin accessibility assays in primary monocytes and monocytic cell lines

    PMID:34017121

    Open questions at the time
    • Relative contribution of CTSG versus ELANE and PRTN3 to H3 cleavage not individually resolved
    • How a granule-associated protease accesses nuclear chromatin is not addressed
    • Downstream transcriptional consequences of H3ΔN priming not fully mapped
  3. 2023 Medium

    Gain- and loss-of-function in colorectal cancer placed CTSG upstream of the Akt/mTOR/Bcl2 axis, establishing a tumor-suppressive role distinct from its myeloid functions.

    Evidence CTSG overexpression and knockdown in CRC cell lines and xenografts, MK2206 (Akt inhibitor) epistasis, and Western blot of pathway markers

    PMID:37151875

    Open questions at the time
    • Whether CTSG protease activity or a non-catalytic function drives Akt suppression is unresolved
    • Direct molecular target linking CTSG to Akt/mTOR not identified
    • Single-lab finding without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CTSG proteolytic activity is mechanistically connected to its distinct roles in chromatin priming and Akt/mTOR suppression, and what its direct substrates are in each context, remains unresolved.
  • No unifying substrate or mechanism linking myeloid chromatin and CRC signaling roles
  • Mechanism of nuclear access and substrate specificity uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 1
Pathway
R-HSA-4839726 Chromatin organization 1

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Cathepsin G (CTSG), along with neutrophil elastase (ELANE) and proteinase 3 (PRTN3), catalyzes proteolytic cleavage of the histone H3 amino terminus (H3ΔN) in human peripheral blood monocytes. This histone mark is abundant in monocytes and becomes largely undetectable upon differentiation into macrophages, correlating with NSP repression. Simultaneous depletion of all three NSPs in monocytic cells caused H3ΔN loss and increased chromatin accessibility, implicating CTSG-mediated H3 cleavage as an epigenetic mechanism that primes chromatin during monocyte-to-macrophage differentiation. Integrative epigenomic analysis, NSP depletion (loss-of-function), chromatin accessibility assays, and identification of H3ΔN as a substrate of CTSG/ELANE/PRTN3 in primary monocytes and monocytic cell lines Nature immunology High 34017121
2023 CTSG overexpression suppressed colorectal cancer (CRC) cell proliferation and tumor growth in vitro and in vivo, acting via suppression of Akt/mTOR signaling and elevation of apoptotic markers including Bcl2 downregulation. Pharmacological inhibition of Akt (MK2206) abolished the pro-survival effects of CTSG silencing, placing CTSG upstream of the Akt/mTOR/Bcl2 anti-apoptotic axis. Gain- and loss-of-function experiments (CTSG overexpression and knockdown) in CRC cell lines and xenograft models; Akt inhibitor (MK2206) epistasis; Western blot for pathway markers International journal of biological sciences Medium 37151875
2012 CTSG regulatory elements drive expression of PML-RARA not only in promyelocytes but also in hematopoietic stem/progenitor cells (KLS: Kit+Lin−Sca+) in Ctsg-PML-RARA transgenic mice. Endogenous Ctsg is expressed in KLS cells, and PML-RARA targeted to the Ctsg locus exerts biological effects on multi-lineage competitive repopulation and alters the transcriptional signature of early myeloid progenitors (CMPs and GMPs), demonstrating that CTSG is expressed and functionally active in multipotent progenitors, not solely in promyelocytes. Transgenic mouse model (Ctsg-PML-RARA knockin), purified HSPC and progenitor cell analysis, competitive repopulation assays, transcriptome analysis of sorted myeloid progenitors PloS one Medium 23056333

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 CG dinucleotide suppression enables antiviral defence targeting non-self RNA. Nature 332 28953888
2015 MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome. Proceedings of the National Academy of Sciences of the United States of America 228 25870282
1998 CG island methylation changes near the GSTP1 gene in prostatic intraepithelial neoplasia. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 227 9641498
1999 Characterization of a novel giant scaffolding protein, CG-NAP, that anchors multiple signaling enzymes to centrosome and the golgi apparatus. The Journal of biological chemistry 216 10358086
2002 Centrosomal proteins CG-NAP and kendrin provide microtubule nucleation sites by anchoring gamma-tubulin ring complex. Molecular biology of the cell 191 12221128
2015 Non-CG Methylation in the Human Genome. Annual review of genomics and human genetics 173 26077819
1990 Isolation of TSH and LH/CG receptor cDNAs from human thyroid: regulation by tissue specific splicing. Molecular endocrinology (Baltimore, Md.) 161 2293030
2014 Dnmt1-independent CG methylation contributes to nucleosome positioning in diverse eukaryotes. Cell 136 24630728
2014 Mutation of a major CG methylase in rice causes genome-wide hypomethylation, dysregulated genome expression, and seedling lethality. Proceedings of the National Academy of Sciences of the United States of America 128 25002488
2019 Structure of the zinc-finger antiviral protein in complex with RNA reveals a mechanism for selective targeting of CG-rich viral sequences. Proceedings of the National Academy of Sciences of the United States of America 112 31719195
2015 CG gene body DNA methylation changes and evolution of duplicated genes in cassava. Proceedings of the National Academy of Sciences of the United States of America 111 26483493
1988 Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides. American journal of human genetics 107 2833855
2018 Mechanistic insights into plant SUVH family H3K9 methyltransferases and their binding to context-biased non-CG DNA methylation. Proceedings of the National Academy of Sciences of the United States of America 95 30150382
1995 Interaction of cA-kinase and cG-kinase in mediating relaxation of dispersed smooth muscle cells. The American journal of physiology 90 7840145
2021 COVID-19 CG enables SARS-CoV-2 mutation and lineage tracking by locations and dates of interest. eLife 88 33620031
1998 Coexpression of gonadotropic hormones and their corresponding FSH- and LH/CG-receptors in the human prostate. The Prostate 79 9582090
2004 The role of MET1 in RNA-directed de novo and maintenance methylation of CG dinucleotides. Plant molecular biology 76 15604652
2002 Trialkyltin compounds enhance human CG secretion and aromatase activity in human placental choriocarcinoma cells. The Journal of clinical endocrinology and metabolism 76 12050258
2000 Association of immature hypophosphorylated protein kinase cepsilon with an anchoring protein CG-NAP. The Journal of biological chemistry 76 10945988
2017 Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors. Scientific reports 74 28424471
1992 Expression of the LH/CG receptor gene in rat ovarian tissue is regulated by an extensive alternative splicing of the primary transcript. Molecular and cellular endocrinology 67 1353463
2012 CG methylation. Epigenomics 66 23244310
2007 CG dinucleotide clustering is a species-specific property of the genome. Nucleic acids research 62 17932072
2001 The role of chorionic gonadotropin (CG) in blastocyst implantation. Archives of medical research 62 11750740
2021 Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation. Nature immunology 59 34017121
2018 Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA. The Journal of biological chemistry 59 29567833
1983 Conformational analysis of a hybrid DNA-RNA double helical oligonucleotide in aqueous solution: d(CG)r(CG)d(CG) studied by 1D- and 2D-1H NMR spectroscopy. Journal of biomolecular structure & dynamics 57 6086057
2008 The structures of non-CG-repeat Z-DNAs co-crystallized with the Z-DNA-binding domain, hZ alpha(ADAR1). Nucleic acids research 55 19074195
2013 Intronic non-CG DNA hydroxymethylation and alternative mRNA splicing in honey bees. BMC genomics 53 24079845
2007 Biochemical characterization and modulation of LH/CG-receptor during human trophoblast differentiation. Journal of cellular physiology 53 17458905
2020 Transposon age and non-CG methylation. Nature communications 51 32144266
2021 Neuronal non-CG methylation is an essential target for MeCP2 function. Molecular cell 45 33561390
2019 Establishment, maintenance, and biological roles of non-CG methylation in plants. Essays in biochemistry 45 31652316
2018 Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation. Neurobiology of aging 44 29631215
1993 Structural influence of RNA incorporation in DNA: quantitative nuclear magnetic resonance refinement of d(CG)r(CG)d(CG) and d(CG)r(C)d(TAGCG). Biochemistry 44 7683912
2017 Allele-specific non-CG DNA methylation marks domains of active chromatin in female mouse brain. Proceedings of the National Academy of Sciences of the United States of America 43 28320934
1995 Distinct CG and CNG DNA methyltransferases in Pisum sativum. The Plant journal : for cell and molecular biology 41 7757118
2021 Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation. Nature communications 40 33602921
2016 Cooperation between the H3K27me3 Chromatin Mark and Non-CG Methylation in Epigenetic Regulation. Plant physiology 37 27535791
1994 CG-1, a parsley light-induced DNA-binding protein. Plant molecular biology 37 8075408
2023 Facilitating CG Simulations with MAD: The MArtini Database Server. Journal of chemical information and modeling 36 36656159
2019 CG dinucleotides enhance promoter activity independent of DNA methylation. Genome research 36 30709850
2015 Mycoplasma CG- and GATC-specific DNA methyltransferases selectively and efficiently methylate the host genome and alter the epigenetic landscape in human cells. Epigenetics 35 25695131
2016 Non-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells. Nature communications 34 26822956
2013 Cg-SoxE and Cg-β-catenin, two new potential actors of the sex-determining pathway in a hermaphrodite lophotrochozoan, the Pacific oyster Crassostrea gigas. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 34 24120488
1997 Expression of Krox proteins during differentiation of the O-2A progenitor cell line CG-4. Journal of neurochemistry 34 9109517
1996 The LH/CG and FSH receptors: different molecular forms and intracellular traffic. Molecular and cellular endocrinology 33 9027354
2007 Characterization of chitinase-like proteins (Cg-Clp1 and Cg-Clp2) involved in immune defence of the mollusc Crassostrea gigas. The FEBS journal 31 17608806
2023 NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons. Molecular cell 30 37098340
2023 CTSG Suppresses Colorectal Cancer Progression through Negative Regulation of Akt/mTOR/Bcl2 Signaling Pathway. International journal of biological sciences 30 37151875
2003 Altering dietary protein type and quantity reduces urinary albumin excretion without affecting plasma glucose concentrations in BKS.cg-m +Lepr db/+Lepr db (db/db) mice. The Journal of nutrition 30 12612136
2021 Deciphering the synergistic and redundant roles of CG and non-CG DNA methylation in plant development and transposable element silencing. The New phytologist 29 34655488
2009 Mutational analysis of the CG recognizing DNA methyltransferase SssI: insight into enzyme-DNA interactions. Biochimica et biophysica acta 29 19654054
2005 Centrosome-targeting region of CG-NAP causes centrosome amplification by recruiting cyclin E-cdk2 complex. Genes to cells : devoted to molecular & cellular mechanisms 29 15670215
2021 Empagliflozin Induces White Adipocyte Browning and Modulates Mitochondrial Dynamics in KK Cg-Ay/J Mice and Mouse Adipocytes. Frontiers in physiology 28 34777009
2019 HTLV-1 contains a high CG dinucleotide content and is susceptible to the host antiviral protein ZAP. Retrovirology 28 31842935
2015 DNA METHYLTRANSFERASE 1 is involved in (m)CG and (m)CCG DNA methylation and is essential for sporophyte development in Physcomitrella patens. Plant molecular biology 27 25944663
2021 Bioinformatics Analyses Indicate That Cathepsin G (CTSG) is a Potential Immune-Related Biomarker in Oral Squamous Cell Carcinoma (OSCC). OncoTargets and therapy 26 33658795
2020 DNA methylation mutants in Physcomitrella patens elucidate individual roles of CG and non-CG methylation in genome regulation. Proceedings of the National Academy of Sciences of the United States of America 26 33376225
2018 Profiling of aberrant DNA methylation in acute myeloid leukemia reveals subclasses of CG-rich regions with epigenetic or genetic association. Leukemia 25 29925905
2017 Gene-body CG methylation and divergent expression of duplicate genes in rice. Scientific reports 24 28572585
2002 Gene structure and expression of cg-ALR1, a type I activin-like receptor from the bivalve mollusc Crassostrea gigas. Gene 24 12490320
2011 Human nucleosomes: special role of CG dinucleotides and Alu-nucleosomes. BMC genomics 22 21627783
2001 Mitogen-activated protein kinase signalling in oligodendrocytes: a comparison of primary cultures and CG-4. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 22 11378302
2001 Differentiation of bipolar CG-4 line oligodendrocytes is associated with regulation of CREB, MAP kinase and PKC signalling pathways. Neuroscience research 21 11672834
1998 Gene, interaction, signal generation, signal divergence and signal transduction of the LH/CG receptor. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 21 29645260
2020 Developmental remodelling of non-CG methylation at satellite DNA repeats. Nucleic acids research 20 33271598
2011 The ncgl1108 (PheP (Cg)) gene encodes a new L-Phe transporter in Corynebacterium glutamicum. Applied microbiology and biotechnology 20 21468701
2020 Identification of fetal unmodified and 5-hydroxymethylated CG sites in maternal cell-free DNA for non-invasive prenatal testing. Clinical epigenetics 19 33081811
2019 Structural analyses reveal that MBD3 is a methylated CG binder. The FEBS journal 19 30980593
2016 Conserved hemopoietic transcription factor Cg-SCL delineates hematopoiesis of Pacific oyster Crassostrea gigas. Fish & shellfish immunology 19 26915307
2004 Homology modeling of the CG-specific DNA methyltransferase SssI and its complexes with DNA and AdoHcy. Journal of biomolecular structure & dynamics 19 15473707
2019 CG hypomethylation leads to complex changes in DNA methylation and transpositional burst of diverse transposable elements in callus cultures of rice. The Plant journal : for cell and molecular biology 18 31529551
2018 Loss of CG Methylation in Marchantia polymorpha Causes Disorganization of Cell Division and Reveals Unique DNA Methylation Regulatory Mechanisms of Non-CG Methylation. Plant & cell physiology 18 30102384
2016 Bioassays for TSH Receptor Autoantibodies, from FRTL-5 Cells to TSH Receptor-LH/CG Receptor Chimeras: The Contribution of Leonard D. Kohn. Frontiers in endocrinology 17 27504107
2010 Human non-CG methylation: are human stem cells plant-like? Epigenetics 17 20647766
1997 Interaction, signal generation, signal divergence, and signal transduction of LH/CG and the receptor. Recent progress in hormone research 15 9238862
1996 Molecular mechanism of LH/CG receptor activation. Molecular and cellular endocrinology 15 9027347
2015 Depletion of CG-Specific Methylation in Mycoplasma hyorhinis Genomic DNA after Host Cell Invasion. PloS one 14 26544880
2012 Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice. PloS one 14 23056333
2023 Chlamydia muridarum infection causes bronchointerstitial pneumonia in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Veterinary pathology 13 37434451
2021 Evolution of CG Methylation Maintenance Machinery in Plants. Epigenomes 13 34968368
2021 Pten Regulates Cardiomyocyte Differentiation by Modulating Non-CG Methylation via Dnmt3. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 34247447
2020 Gene body methylation facilitates the transcription of CTSG via antisense lncRNA AL136018.1 in dermatomyositic myoideum. Cell biology international 12 33245176
2023 CG hypermethylation of the bHLH39 promoter regulates its expression and Fe deficiency responses in tomato roots. Horticulture research 11 37577397
2022 Biophysical interaction between lanthanum chloride and (CG)n or (GC)n repeats: A reversible B-to-Z DNA transition. International journal of biological macromolecules 11 35809677
2022 Recognition of 5-methyl-CG and CG base pairs in duplex DNA with high stability using antiparallel-type triplex-forming oligonucleotides with 2-guanidinoethyl-2'-deoxynebularine. Nucleic acids research 11 36454012
2022 Luxeptinib (CG-806) Targets FLT3 and Clusters of Kinases Operative in Acute Myeloid Leukemia. Molecular cancer therapeutics 10 35499387
2020 COVID-19 CG: Tracking SARS-CoV-2 mutations by locations and dates of interest. bioRxiv : the preprint server for biology 10 32995794
2016 Mammalian non-CG methylations are conserved and cell-type specific and may have been involved in the evolution of transposon elements. Scientific reports 10 27573482
1998 Gene, interaction, signal generation, signal divergence and signal transduction of the LH/CG receptor. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 10 9833610
2022 Effect of the Thermal Fluctuations of the Photophysics of GC and CG DNA Steps: A Computational Dynamical Study. The journal of physical chemistry. B 9 36508709
2014 Characterising the atypical 5'-CG DNA sequence specificity of 9-aminoacridine carboxamide Pt complexes. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 9 24827388
2013 Analysis of promoter non-CG methylation in prostate cancer. Epigenomics 9 23414321
2024 TLR7 rs179008 (A/T) and TLR7 rs3853839 (C/G) polymorphisms are associated with variations in IFN-α levels in HTLV-1 infection. Frontiers in immunology 8 39650644
2023 On the prediction of non-CG DNA methylation using machine learning. NAR genomics and bioinformatics 8 37206627
2023 DNA conformational dynamics in the context-dependent non-CG CHH methylation by plant methyltransferase DRM2. The Journal of biological chemistry 8 37926286
2017 Presence of a consensus DNA motif at nearby DNA sequence of the mutation susceptible CG nucleotides. Gene 8 28986316
2003 Expression of beta hCG and alpha CG mRNA and hCG hormone in human decidual tissue in patients during tubal pregnancy. Molecular human reproduction 8 12569177
1996 Structure and functional significance of the carbohydrates of the LH/CG receptor. Molecular and cellular endocrinology 8 9027348

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