Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

• Type of Material: Article
• Authors: Po-Nien Lu, Greenwood Genetic Center; Trevor Moreland, Greenwood Genetic Center; Courtney J. Christian, Emory University; Troy C. Lund, University of Minnesota; Richard A. Steet, Greenwood Genetic Center; Heather Flanagan-Steet, Greenwood Genetic Center
• Language: English
• Date: 2020-10-15
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2020, Lu et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.133019
• Title of Journal or Parent Work: JCI insight
• Volume: 5
• Issue: 20
• Grant/Funding Information: Additionally, we have received funds from the National MPS Society and ISMRD.; This work was supported by an R01 to RS from the NIHGMS GM086524, grants to HFS from the National MPS Society and the ISMRD, as well as a grant to RS by the Yash Ghandi Foundation.
• Keywords: Lysosomes; Development; Proteases; Cardiovascular disease; Cell Biology
• Research Categories: Chemistry, Biochemistry; Health Sciences, Human Development; Biology, Cell; Biology, Genetics

Abstract

Although congenital heart defects (CHDs) represent the most common birth defect, a comprehensive understanding of disease etiology remains unknown. This is further complicated since CHDs can occur in isolation or as a feature of another disorder. Analyzing disorders with associated CHDs provides a powerful platform to identify primary pathogenic mechanisms driving disease. Aberrant localization and expression of cathepsin proteases can perpetuate later-stage heart diseases, but their contribution toward CHDs is unclear. To investigate the contribution of cathepsins during cardiovascular development and congenital disease, we analyzed the pathogenesis of cardiac defects in zebrafish models of the lysosomal storage disorder mucolipidosis II (MLII). MLII is caused by mutations in the GlcNAc-1-phosphotransferase enzyme (Gnptab) that disrupt carbohydrate-dependent sorting of lysosomal enzymes. Without Gnptab, lysosomal hydrolases, including cathepsin proteases, are inappropriately secreted. Analyses of heart development in gnptab-deficient zebrafish show cathepsin K secretion increases its activity, disrupts TGF-β–related signaling, and alters myocardial and valvular formation. Importantly, cathepsin K inhibition restored normal heart and valve development in MLII embryos. Collectively, these data identify mislocalized cathepsin K as an initiator of cardiac disease in this lysosomal disorder and establish cathepsin inhibition as a viable therapeutic strategy.