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

(2016) JOURNAL OF EXPERIMENTAL MEDICINE. 213(10). p.2081-2097
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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 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.
Keywords
TRYPSINOGEN ACTIVATION, CELL-DEATH, INNATE IMMUNITY, AIM2 INFLAMMASOME, NLRP3 INFLAMMASOMES, REGULATES AUTOPHAGY, SIGNALING PATHWAYS, CYTOSOLIC BACTERIA, HUMAN MACROPHAGES, DEFICIENT MICE

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Citation

Please use this url to cite or link to this publication:

Chicago
Qi, Xiaopeng, Si Ming Man, RK Subbarao Malireddi, Rajendra Karki, Christopher Lupfer, Prajwal Gurung, Geoffrey Neale, Clifford S Guy, Mohamed Lamkanfi, and Thirumala-Devi Kanneganti. 2016. “Cathepsin B Modulates Lysosomal Biogenesis and Host Defense Against Francisella Novicida Infection.” Journal of Experimental Medicine 213 (10): 2081–2097.
APA
Qi, Xiaopeng, Man, S. M., Malireddi, R. S., Karki, R., Lupfer, C., Gurung, P., Neale, G., et al. (2016). Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection. JOURNAL OF EXPERIMENTAL MEDICINE, 213(10), 2081–2097.
Vancouver
1.
Qi X, Man SM, Malireddi RS, Karki R, Lupfer C, Gurung P, et al. Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection. JOURNAL OF EXPERIMENTAL MEDICINE. 2016;213(10):2081–97.
MLA
Qi, Xiaopeng, Si Ming Man, RK Subbarao Malireddi, et al. “Cathepsin B Modulates Lysosomal Biogenesis and Host Defense Against Francisella Novicida Infection.” JOURNAL OF EXPERIMENTAL MEDICINE 213.10 (2016): 2081–2097. Print.
@article{8132605,
  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.},
  author       = {Qi, Xiaopeng and Man, Si Ming and Malireddi, RK Subbarao and Karki, Rajendra and Lupfer, Christopher and Gurung, Prajwal and Neale, Geoffrey and Guy, Clifford S and Lamkanfi, Mohamed and Kanneganti, Thirumala-Devi},
  issn         = {0022-1007},
  journal      = {JOURNAL OF EXPERIMENTAL MEDICINE},
  language     = {eng},
  number       = {10},
  pages        = {2081--2097},
  title        = {Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection},
  url          = {http://dx.doi.org/10.1084/jem.20151938},
  volume       = {213},
  year         = {2016},
}

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