PUBLICATION

TGF-ß Regulates Cathepsin Activation during Normal and Pathogenic Development

Authors
Flanagan-Steet, H., Christian, C., Lu, P.N., Aarnio-Peterson, M., Sanman, L., Archer-Hartmann, S., Azadi, P., Bogyo, M., Steet, R.A.
ID
ZDB-PUB-180315-8
Date
2018
Source
Cell Reports   22: 2964-2977 (Journal)
Registered Authors
Flanagan-Steet, Heather, Lu, Po-Nien, Steet, Richard
Keywords
activity-based profiling, cartilage, cathepsin proteases, glycosaminoglycans, glycosylation, lysosomes, mucolipidosis, zebrafish
MeSH Terms
  • Zebrafish
  • Animals
  • Disease Models, Animal
  • Transforming Growth Factor beta/metabolism*
  • Cathepsins/metabolism*
PubMed
29539424 Full text @ Cell Rep.
Abstract
Cysteine cathepsins play roles during development and disease beyond their function in lysosomal protein turnover. Here, we leverage a fluorescent activity-based probe (ABP), BMV109, to track cysteine cathepsins in normal and diseased zebrafish embryos. Using this probe in a model of mucolipidosis II, we show that loss of carbohydrate-dependent lysosomal sorting alters the activity of several cathepsin proteases. The data support a pathogenic mechanism where TGF-ß signals enhance the proteolytic processing of pro-Ctsk by modulating the expression of chondroitin 4-sulfate (C4-S). In MLII, elevated C4-S corresponds with TGF-ß-mediated increases in chst11 expression. Inhibiting chst11 impairs the proteolytic activation of Ctsk and alleviates the MLII phenotypes. These findings uncover a regulatory loop between TGF-ß signaling and Ctsk activation that is altered in the context of lysosomal disease. This work highlights the power of ABPs to identify mechanisms underlying pathogenic development in living animals.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
fb6TgTransgenic Insertion
    ia15TgTransgenic Insertion
      y1TgTransgenic Insertion
        zf2146TgTransgenic Insertion
          1 - 4 of 4
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          Human Disease / Model
          Human Disease Fish Conditions Evidence
          mucolipidosis II alpha/betaWT + MO1-gnptabcontrolTAS
          1 - 1 of 1
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          Sequence Targeting Reagents
          Target Reagent Reagent Type
          chst11MO1-chst11MRPHLNO
          ctskMO1-ctskMRPHLNO
          gnptabMO1-gnptabMRPHLNO
          1 - 3 of 3
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          Fish
          Antibodies
          Name Type Antigen Genes Isotypes Host Organism
          Ab1-ctslmonoclonal
            IgG1Mouse
            Ab1-ctsspolyclonal
              IgGGoat
              Ab1-ctszpolyclonal
                IgGGoat
                Ab1-smadpolyclonalIgGRabbit
                Ab2-acanmonoclonal
                  IgG1Mouse
                  Ab2-cspg4monoclonal
                    IgG1Mouse
                    Ab2-ctskpolyclonal
                      IgGRabbit
                      Ab9-smad2monoclonal
                        IgGRabbit
                        Ab-10E4monoclonal
                          IgMMouse
                          1 - 9 of 9
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                          Orthology
                          No data available
                          Engineered Foreign Genes
                          Marker Marker Type Name
                          CeruleanEFGCerulean
                          EGFPEFGEGFP
                          mCherryEFGmCherry
                          mRFPEFGmRFP
                          1 - 4 of 4
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                          Mapping
                          No data available