ZFIN ID: ZDB-PUB-180315-8
TGF-ß Regulates Cathepsin Activation during Normal and Pathogenic Development
Flanagan-Steet, H., Christian, C., Lu, P.N., Aarnio-Peterson, M., Sanman, L., Archer-Hartmann, S., Azadi, P., Bogyo, M., Steet, R.A.
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:
  • Animals
  • Cathepsins/metabolism*
  • Disease Models, Animal
  • Transforming Growth Factor beta/metabolism*
  • Zebrafish
PubMed: 29539424 Full text @ Cell Rep.
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.