期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 213, 期 10, 页码 2081-2097出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151938
关键词
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资金
- US National Institutes of Health [AI101935, AI124346, AR056296, CA163507]
- American Lebanese Syrian Associated Charities
- European Research Council [281600]
- Fund for Scientific Research-Flanders [G030212N]
- National Health and Medical Research Council of Australia [APP1091544]
- European Research Council (ERC) [281600] Funding Source: European Research Council (ERC)
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.
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