TY - JOUR
T1 - Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection
AU - Qi, Xiaopeng
AU - Man, Si Ming
AU - Malireddi, R. K.Subbarao
AU - Karki, Rajendra
AU - Lupfer, Christopher
AU - Gurung, Prajwal
AU - Neale, Geoffrey
AU - Guy, Clifford S.
AU - Lamkanfi, Mohamed
AU - Kanneganti, Thirumala Devi
N1 - Publisher Copyright:
© 2016 Qi et al.
PY - 2016/9/19
Y1 - 2016/9/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84992192230&partnerID=8YFLogxK
U2 - 10.1084/jem.20151938
DO - 10.1084/jem.20151938
M3 - Article
SN - 0022-1007
VL - 213
SP - 2081
EP - 2097
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -