PUBLICATION

Dysregulated lysosomal exocytosis drives protease-mediated cartilage pathogenesis in multiple lysosomal disorders

Authors
Lee, J.J., Wang, T., Wiggins, K., Lu, P.N., Underwood, C., Ochenkowska, K., Samarut, E., Pollard, L.M., Flanagan-Steet, H., Steet, R.
ID
ZDB-PUB-240318-5
Date
2024
Source
iScience   27: 109293109293 (Journal)
Registered Authors
Flanagan-Steet, Heather, Lu, Po-Nien, Samarut, Eric, Steet, Richard, Wang, Tong, Wiggins, Kali
Keywords
Cell biology, Developmental biology, Molecular biology
MeSH Terms
none
PubMed
38495824 Full text @ iScience
Abstract
The classic view of the lysosome as a static recycling center has been replaced with one of a dynamic and mobile hub of metabolic regulation. This revised view raises new questions about how dysfunction of this organelle causes pathology in inherited lysosomal disorders. Here we provide evidence for increased lysosomal exocytosis in the developing cartilage of three lysosomal disease zebrafish models with distinct etiologies. Dysregulated exocytosis was linked to altered cartilage development, increased activity of multiple cathepsin proteases, and cathepsin- and TGFβ-mediated pathogenesis in these models. Moreover, inhibition of cathepsin activity or direct blockade of exocytosis with small molecule modulators improved the cartilage phenotypes, reinforcing a connection between excessive extracellular protease activity and cartilage pathogenesis. This study highlights the pathogenic consequences in early cartilage development arising from uncontrolled release of lysosomal enzymes via exocytosis, and suggests that pharmacological enhancement of this process could be detrimental during tissue development.
Genes / Markers
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ggc10d
    		Small Deletion
    pd1064TgTransgenic Insertion
      y1TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        ctsaMO1-ctsaMRPHLNO
        galnsMO1-galnsMRPHLNO
        gnptabMO1-gnptabMRPHLNO
        gnptabMO3-gnptabMRPHLNO
        lamp1aMO1-lamp1aMRPHLNO
        lamp1bMO1-lamp1bMRPHLNO
        neu1CRISPR1-neu1CRISPR
        neu1CRISPR2-neu1CRISPR
        neu1CRISPR3-neu1CRISPR
        neu1CRISPR4-neu1CRISPR
        1 - 10 of 16
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        Fish
        No data available
        Antibodies
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        RFPEFGRFP
        1 - 2 of 2
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        Mapping
        No data available
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        Citation
        Lee, J.J., Wang, T., Wiggins, K., Lu, P.N., Underwood, C., Ochenkowska, K., Samarut, E., Pollard, L.M., Flanagan-Steet, H., Steet, R. (2024) Dysregulated lysosomal exocytosis drives protease-mediated cartilage pathogenesis in multiple lysosomal disorders. iScience. 27:109293109293.