PUBLICATION

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

Authors
Lu, P.N., Moreland, T., Christian, C.J., Lund, T.C., Steet, R.A., Flanagan-Steet, H.
ID
ZDB-PUB-201020-13
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
  • Humans
  • Zebrafish/genetics
  • Genetic Predisposition to Disease
  • Animals
  • Mutation
  • Enzyme Activation/genetics
  • Transforming Growth Factor beta/genetics
  • Cathepsin K/genetics*
  • Transferases (Other Substituted Phosphate Groups)/genetics*
  • Disease Models, Animal
  • Heart Valves/growth & development
  • Mucolipidoses/genetics*
  • Mucolipidoses/physiopathology
  • Heart/growth & development*
  • Heart/physiopathology
  • Heart Defects, Congenital/genetics*
  • Heart Defects, Congenital/physiopathology
  • Lysosomal Storage Diseases/genetics
  • Lysosomal Storage Diseases/physiopathology
(all 19)
PubMed
33055423 Full text @ JCI Insight
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.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
acanaf1Tg/f1Tg + MO1-gnptabstandard conditionsDay 4ISH
acanaf1Tg/f1Tg + MO2-gnptabstandard conditionsDay 4ISH
acanagnptabga2/ga2standard conditionsDay 4ISH
ctskf1Tg/f1Tgstandard conditionsLong-pecRTPCR
ctskf1Tg/f1Tgstandard conditionsProtruding-mouthRTPCR
ctsks849Tg/s849Tgstandard conditionsProtruding-mouthRTPCR
ctsks849Tg/s849Tgstandard conditionsLong-pecRTPCR
ctslaf1Tg/f1Tgstandard conditionsLong-pecRTPCR
ctslaf1Tg/f1Tgstandard conditionsProtruding-mouthRTPCR
ctslas849Tg/s849Tgstandard conditionsLong-pecRTPCR
1 - 10 of 57
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Phenotype
Fish Conditions Stage Phenotype Figure
ABchemical treatment by environment: EC 3.4.22.38 (cathepsin K) inhibitorDay 4
ABchemical treatment by environment: EC 3.4.22.38 (cathepsin K) inhibitorDay 4
AB + MO1-gnptabstandard conditionsDay 4
AB + MO1-gnptabstandard conditionsDay 4
AB + MO1-gnptabchemical treatment by environment: EC 3.4.22.38 (cathepsin K) inhibitorDay 4
AB + MO1-gnptabchemical treatment by environment: EC 3.4.22.38 (cathepsin K) inhibitorDay 4
AB + MO2-gnptabstandard conditionsDay 4
AB + MO2-gnptabstandard conditionsDay 4
AB + MO2-gnptabchemical treatment by environment: EC 3.4.22.38 (cathepsin K) inhibitorDay 4
AB + MO2-gnptabchemical treatment by environment: EC 3.4.22.38 (cathepsin K) inhibitorDay 4
1 - 10 of 118
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
bw8TgTransgenic Insertion
    f1TgTransgenic Insertion
      ga1
        		Small Deletion
        ga2
          		Small Deletion
          ga3
            		Small Deletion
            ggc1
              		Indel
              ggc2
                		Small Deletion
                ggc3TgTransgenic Insertion
                  ia16TgTransgenic Insertion
                    mw29TgTransgenic Insertion
                      1 - 10 of 12
                      Show
                      Human Disease / Model
                      Human Disease Fish Conditions Evidence
                      congenital heart diseasegnptabga2/ga2standard conditionsTAS
                      congenital heart diseasegnptabga3/ga3standard conditionsTAS
                      1 - 2 of 2
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                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      ctskTALEN1-ctskTALEN
                      gnptabMO1-gnptabMRPHLNO
                      gnptabMO2-gnptabMRPHLNO
                      gnptabTALEN1-gnptabTALEN
                      1 - 4 of 4
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                      Fish
                      Fish
                      AB
                      AB + MO1-gnptab
                      AB + MO2-gnptab
                      ctskggc1/ggc1
                      ctskggc2/ggc2
                      f1Tg/f1Tg
                      f1Tg/f1Tg + MO1-gnptab
                      f1Tg/f1Tg + MO2-gnptab
                      f1Tg/f1Tg; mw29Tg/mw29Tg + MO1-gnptab
                      f1Tg/f1Tg; mw29Tg/mw29Tg + MO2-gnptab
                      1 - 10 of 20
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                      Antibodies
                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      EGFPEFGEGFP
                      GAL4EFGGAL4
                      GFPEFGGFP
                      RFPEFGRFP
                      1 - 4 of 4
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                      Mapping
                      No data available
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                      Citation
                      Lu, P.N., Moreland, T., Christian, C.J., Lund, T.C., Steet, R.A., Flanagan-Steet, H. (2020) Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation. JCI insight. 5(20):.