TGF-ß Regulates Cathepsin Activation during Normal and Pathogenic Development

Publication date: 13 March 2018
Source:Cell Reports, Volume 22, Issue 11
Author(s): Heather Flanagan-Steet, Courtney Christian, Po-Nien Lu, Megan Aarnio-Peterson, Laura Sanman, Stephanie Archer-Hartmann, Parastoo Azadi, Matthew Bogyo, Richard A. Steet
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.

Graphical abstract

Teaser

Chondroitin sulfate is a known regulator of cathepsin protease activity. Flanagan-Steet et al. identify a positive feedback mechanism whereby cathepsins secreted from chondrocytes upon loss of lysosomal targeting activate TGF-ß signaling in developing cartilage. This increased signaling, in turn, stimulates chondroitin-4 sulfation and enhances cathepsin activity.


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