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.
© 2016 Qi, Xiaopeng, et al. Originally published in Journal of Experimental Medicine. DOI: https://doi.org/10.1084/jem.20151938
Infectious disease and host defense, Innate immunity and inflammation
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. "Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection." Journal of Experimental Medicine 213, no. 10 (2016): 2081-2097.
Journal of Experimental Medicine