ZFIN ID: ZDB-PUB-201020-13
Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation
Lu, P.N., Moreland, T., Christian, C.J., Lund, T.C., Steet, R.A., Flanagan-Steet, H.
Date: 2020
Source: JCI insight   5(20): (Journal)
Registered Authors: Flanagan-Steet, Heather, Lu, Po-Nien, Steet, Richard
Keywords: Cardiovascular disease, Cell Biology, Development, Lysosomes, Proteases
MeSH Terms:
  • Animals
  • Cathepsin K/genetics*
  • Disease Models, Animal
  • Enzyme Activation/genetics
  • Genetic Predisposition to Disease
  • Heart/growth & development*
  • Heart/physiopathology
  • Heart Defects, Congenital/genetics*
  • Heart Defects, Congenital/physiopathology
  • Heart Valves/growth & development
  • Humans
  • Lysosomal Storage Diseases/genetics
  • Lysosomal Storage Diseases/physiopathology
  • Mucolipidoses/genetics*
  • Mucolipidoses/physiopathology
  • Mutation
  • Transferases (Other Substituted Phosphate Groups)/genetics*
  • Transforming Growth Factor beta/genetics
  • Zebrafish/genetics
PubMed: 33055423 Full text @ JCI Insight
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.