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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Citations (Scopus)

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 TRP ML1. 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.

Original languageEnglish
Pages (from-to)2081-2097
Number of pages17
JournalJournal of Experimental Medicine
Volume213
Issue number10
DOIs
Publication statusPublished - 19 Sept 2016
Externally publishedYes

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