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Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

ABSTRACT: Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell.

ORGANISM(S): Mus musculus

PROVIDER: GSE79508 | GEO | 2016/08/04

SECONDARY ACCESSION(S): PRJNA316012

REPOSITORIES: GEO

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Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.

2016-08-04 | E-GEOD-79508 | biostudies-arrayexpress

Cathepsin L is required for autolysosomal clearance in Drosophila

Project description:Autophagy is a highly conserved lysosomal degrative pathway important for maintaining cellular homeostasis. Much of our current knowledge of autophagy is focused on the initiation steps with the later steps, particularly lysosomal fusion leading to autolysosome formation and the subsequent role of lysosomal enzymes in degradation and recycling become evident. Autophagy can function in both cell survival and cell death, however the mechanisms that distinguish adaptive/survival autophagy from autophagy-dependent cell death remains to be established. Here we use a proteomic analysis of larval midguts during degradation identifying a group of proteins with peptidase activity, suggesting a role in autophagy-dependent cell death. We show that Cathepsin L deficient Drosophila larval midgut cells, accumulate autophagic vesicles due to a block in autophagic flux, yet midgut degradation in not compromised. The accumulation of large aberrant autolysosomes in the absence of Cathepsin function appears to be the consequence of decreased degradative capacity as they contain undigested cytoplasmic material rather and not due to a defect in autophagosome-lysosome fusion. Finally, we find that other Cathepsins are also required for proper autolysosomal degradation in Drosophila larval midgut cells and that this is conserved in mammalian cells. Our findings suggest that Cathepsins play an important degrative role in the autolysosome to maintain autophagy flux, by balancing autophagosome production and turnover (to prevent autophagic stress).

2022-02-15 | PXD016675 | Pride

Intra-macrophage Expression data of Francisella tularensis novicida U112

2017-05-02 | GSE75689 | GEO

Mus musculus

Project description:Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

| PRJNA316012 | ENA

Altered Ca+2 homeostasis induces Calpain-Cathepsin axis activation in sCJD.

Project description:Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrPSc). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca+2) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis. Here we describe the presence of massive regulation of Ca+2 responsive genes in sCJD brain tissue, accompanied by two Ca+2-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Calpain 1 treatment enhances seeding activity of PrPSc in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons. Additionally, massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca+2 homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model. Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.

2017-05-15 | GSE90977 | GEO

Intra-macrophage Expression data of Francisella tularensis novicida U112

Project description:These samples are part of an experiment comparing the expression profiles of Francisella tularensis novicida grown in chemically defined medium and bacteria isolated 24 hours post infection of J774 macrophages to identify virulence factors Custom microarray submitted previously was used as the platform (GPL20119). The samples submitted here were compared with samples submitted previously (GSM1673555-57 in GSE68478) and differentially expressed genes during the intra-macrophage growth were identified.

2017-05-02 | E-GEOD-75689 | biostudies-arrayexpress

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Project description:Francisella novicida FTN1465 knock-out mutant was compared to wild type bacteria.

2007-05-23 | E-MEXP-1105 | biostudies-arrayexpress

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Project description:Francisella cf. novicida Fx1 genome sequencing project.

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Effect of Cathepsin L exposure on endothelial cell transcriptomics

Project description:Cathepsin L is a lysosomal protease that is secreted by several cancer cells. Cathepsin L upregulation has been widely associated with poor clinical outcome and increased metastatic incidence. However, whether Cathepsin L participates in tumor angiogenesis remains less studied. Our study showed a significant activation of angiogenic capacity of endothelial cells in presence of purified or tumor derived Cathepsin L. In addition, Cathepsin L exposure led to a significant increase in the proliferative capacity of endothelial cells. While the ability of Cathepsin L to promote endothelial cell sprouting, migration, invasion and tube formation can be attributed to its proteolytic effects on extracellular matrix, how it promotes endothelial cell proliferation remains obscure. The objective of this study was to test if Cathepsin L exposure can activate signaling cascades and gene expression leading to proliferation of endothelial cells.

2016-06-20 | GSE75744 | GEO

Francisella tularensis subsp. novicida U112

Project description:Francisella tularensis subsp. novicida sRNA sequencing

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