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

Xiaopeng Qi; Si Ming Man; R K Subbarao Malireddi; Rajendra Karki; Christopher Lupfer; Prajwal Gurung; Geoffrey Neale; Clifford S Guy; Mohamed Lamkanfi; Thirumala-Devi Kanneganti

doi:10.1084/jem.20151938

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

Journal article

Open access

Peer reviewed

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

Xiaopeng Qi, Si Ming Man, R K Subbarao Malireddi, Rajendra Karki, Christopher Lupfer, Prajwal Gurung, Geoffrey Neale, Clifford S Guy, Mohamed Lamkanfi and Thirumala-Devi Kanneganti

The Journal of experimental medicine, Vol.213(10), pp.2081-2097

09/19/2016

DOI: 10.1084/jem.20151938

PMCID: PMC5030800

PMID: 27551156

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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.

Up-Regulation

Gram-Negative Bacterial Infections - enzymology

Gram-Negative Bacterial Infections - immunology

NF-kappa B - metabolism

Extracellular Signal-Regulated MAP Kinases - metabolism

Autophagy

Gram-Negative Bacterial Infections - microbiology

Organelle Biogenesis

Lysosomes - metabolism

Transient Receptor Potential Channels - metabolism

Macrophages - ultrastructure

Signal Transduction

Down-Regulation

Mice, Inbred C57BL

Bone Marrow Cells - pathology

Francisella - immunology

Cathepsin B - metabolism

Host-Pathogen Interactions

Macrophages - metabolism

Animals

Intracellular Space - microbiology

Models, Biological

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism

Enzyme Activation

Ion Channel Gating

Details

Title: Subtitle: Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection
Creators: Xiaopeng Qi - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
Si Ming Man - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
R K Subbarao Malireddi - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
Rajendra Karki - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
Christopher Lupfer - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
Prajwal Gurung - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
Geoffrey Neale - Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105
Clifford S Guy - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
Mohamed Lamkanfi - Inflammation Research Center, VIB, B-9052 Zwijnaarde-Ghent, Belgium Department of Internal Medicine, Ghent University, B-9000 Ghent, Belgium
Thirumala-Devi Kanneganti - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105 thirumala-devi.kanneganti@stjude.org
Resource Type: Journal article
Publication Details: The Journal of experimental medicine, Vol.213(10), pp.2081-2097
DOI: 10.1084/jem.20151938
PMID: 27551156
PMCID: PMC5030800
ISSN: 0022-1007
eISSN: 1540-9538
Grant note: R01 AI101935 / NIAID NIH HHS R01 AR056296 / NIAMS NIH HHS R37 AI101935 / NIAID NIH HHS R01 CA163507 / NCI NIH HHS R01 AI124346 / NIAID NIH HHS
Language: English
Date published: 09/19/2016
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984094664402771

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