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

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.

Osteoblast cell death triggers a pro-osteogenic inflammatory response regulated by reactive oxygen species and glucocorticoid signaling in zebrafish

“…A similar process was suggested to take place in medaka fish, in which RANKL (Receptor activator of NF-κB ligand) was ubiquitously overexpressed . Some caution is warranted, as ctsK also labels mesenchymal cells in some tissues (Debnath et al, 2018;Lu et al, 2020) and we observed immobile ctsk:nlsmCherry+ nuclei at a distance from the opercle, in locations unlikely to contain osteoclasts (data not shown). It is noteworthy that conversion of macrophages to osteoclasts depends on inflammatory signals such as Tnf-α .…”

ROS signaling-induced mitochondrial Sgk1 regulates epithelial cell plasticity

“…10A-B). The involvement of autophagy was further investigated using the autophagy defective gnptab -/- zebrafish (Lu et al, 2020; Willet et al, 2018). No difference was detected in NaR cell reactivation between gnptab -/- fish and their siblings, indicating that autophagy does not play a major role in NaR cell reactivation (Supplemental Figs.…”

“…The noa mutant line, dlat -/- (Taylor et al, 2004) was obtained from the Zebrafish International Resource Center (ZIRC). Mutant gnptab -/- fish were obtained from Dr. Heather Flanagan-Steet, Clemson University (Lu et al, 2020). The fish were genotyped as previously reported (Liu et al, 2020; Xin et al, 2019).…”

GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

“…Previous studies have successfully established zebrafish models to study LSDs, including mucolipidosis type II [45][46][47][48] . Since our data indicated that GCAF is required for the cleavage and activation of GNPT α/β precursor, we asked if their knockouts share similar developmental defects in zebrafish.…”