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

J Exp Med. 2016 Sep 19;213(10):2081-97. doi: 10.1084/jem.20151938. Epub 2016 Aug 22.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Bone Marrow Cells / pathology
  • Cathepsin B / metabolism*
  • Down-Regulation
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Francisella / immunology*
  • Gram-Negative Bacterial Infections / enzymology
  • Gram-Negative Bacterial Infections / immunology*
  • Gram-Negative Bacterial Infections / microbiology*
  • Host-Pathogen Interactions*
  • Intracellular Space / microbiology
  • Ion Channel Gating
  • Lysosomes / metabolism*
  • Macrophages / metabolism
  • Macrophages / ultrastructure
  • Mice, Inbred C57BL
  • Models, Biological
  • NF-kappa B / metabolism
  • Organelle Biogenesis*
  • Signal Transduction
  • Transient Receptor Potential Channels / metabolism
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Mcoln1 protein, mouse
  • NF-kappa B
  • Tcfeb protein, mouse
  • Transient Receptor Potential Channels
  • Extracellular Signal-Regulated MAP Kinases
  • Cathepsin B