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

Po Nien Lu, Trevor Moreland, Courtney J. Christian, Troy C. Lund, Richard A. Steet, Heather Flanagan-Steet

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere133019
JournalJCI Insight
Issue number20
StatePublished - Oct 15 2020

Bibliographical note

Funding Information:
in the diseased valves of MPSVII dogs, as well as the hearts of MPSI mice (53). Baldo and coworkers further demonstrated that inhibiting cathepsin B in MPSI mice improves but does not completely normalize cardiac function (52). In both studies, the basis for increased cathepsin expression was not clear but was suggested to possibly arise from immune activation in these tissues (52, 54). The present work defines a pathogenic role for cathepsin K, uncovering insight into the basis for its increased activity by demonstrating that enzyme secretion itself enhances processing and activation. This pathogenic scenario appears distinct from previously described MPS disorders, as it is mediated at the level of localization and activation — not abnormal expression. This is supported by prior work that found no difference in ctsk transcript abundance in MLII zebrafish embryos, supporting a posttranscriptional mode of enzyme dysregulation (32).

Publisher Copyright:
Copyright: © 2020, Lu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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