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| Status |
Public on Aug 04, 2016 |
| Title |
Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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.
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| Contributor(s) |
Man SM, Neale G, Qi X, Malireddi RK, Karki R, Lupfer C, Gurung P, Guy C, Lamkanfi M, Kanneganti TD |
| Citation(s) |
27551156 |
| Submission date |
Mar 22, 2016 |
| Last update date |
Feb 21, 2018 |
| Contact name |
Geoffrey Neale |
| E-mail(s) |
geoffrey.neale@stjude.org
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| Organization name |
St Jude Childrens Research Hospital
|
| Department |
Hartwell Center
|
| Street address |
262 Danny Thomas Place
|
| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38105 |
| Country |
USA |
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| Platforms (1) |
| GPL16570 |
[MoGene-2_0-st] Affymetrix Mouse Gene 2.0 ST Array [transcript (gene) version] |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA316012 |
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