title: 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 diseases in humans. In this study, 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 down-regulated mechanistic target of rapamycin activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via transcription factor EB, 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 populations and basic recycling functions in the cell.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Xiaopeng
authors.identifier: 0000-0002-5280-8445
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Si Ming
authors.identifier: 0000-0002-5079-2857
authors.initials: SM
authors.lastname: Man
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: R K Subbarao
authors.initials: RK
authors.lastname: Malireddi
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Karki
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lupfer
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Prajwal
authors.initials: P
authors.lastname: Gurung
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Geoffrey
authors.identifier: 0000-0003-3776-0858
authors.initials: G
authors.lastname: Neale
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Clifford S
authors.identifier: 0000-0001-7486-7107
authors.initials: CS
authors.lastname: Guy
authors.affiliation: Inflammation Research Center, VIB, B-9052 Zwijnaarde-Ghent, Belgium Department of Internal Medicine, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105 thirumala-devi.kanneganti@stjude.org.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001854:Bone Marrow Cells / Q000473:pathology; D002401:Cathepsin B / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005603:Francisella / Q000276:immunology*; D016905:Gram-Negative Bacterial Infections / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology*; D054884:Host-Pathogen Interactions; D042541:Intracellular Space / Q000382:microbiology; D015640:Ion Channel Gating; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D001678:Organelle Biogenesis; D015398:Signal Transduction; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C512321:Mcoln1 protein, mouse; D016328:NF-kappa B; C484068:Tcfeb protein, mouse; D050051:Transient Receptor Potential Channels; D048049:Extracellular Signal-Regulated MAP Kinases; D002401:Cathepsin B