2. Academic Validation
  3. Pressure sensing of lysosomes enables control of TFEB responses in macrophages

Pressure sensing of lysosomes enables control of TFEB responses in macrophages

  • Nat Cell Biol. 2024 Jul 12. doi: 10.1038/s41556-024-01459-y.
Ruiqi Cai 1,  Ori Scott 1,  Gang Ye 1,  Trieu Le 1,  Ekambir Saran 1,  Whijin Kwon 1,  Subothan Inpanathan 2 3,  Blayne A Sayed 1,  Roberto J Botelho 2 3,  Amra Saric 4 5,  Stefan Uderhardt 6 7 8,  Spencer A Freeman 9 10
Affiliations

Affiliations

  • 1 Program in Cell Biology and Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 2 Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, Ontario, Canada.
  • 3 Molecular Science Graduate Program, Toronto Metropolitan University, Toronto, Ontario, Canada.
  • 4 Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • 5 Program in Neurosciences and Mental Health, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 6 Department of Internal Medicine, Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen, Erlangen, Germany.
  • 7 Deutsches Zentrum für Immuntherapie, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen, Erlangen, Germany.
  • 8 Exploratory Research Unit, Optical Imaging Centre Erlangen, Friedrich-Alexander University Erlangen, Erlangen, Germany.
  • 9 Program in Cell Biology and Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Ontario, Canada. spencer.freeman@sickkids.ca.
  • 10 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. spencer.freeman@sickkids.ca.
PMID: 38997458 DOI: 10.1038/s41556-024-01459-y
Abstract

Polymers are endocytosed and hydrolysed by lysosomal Enzymes to generate transportable solutes. While the transport of diverse organic solutes across the plasma membrane is well studied, their necessary ongoing efflux from the endocytic fluid into the cytosol is poorly appreciated by comparison. Myeloid cells that employ specialized types of endocytosis, that is, phagocytosis and macropinocytosis, are highly dependent on such transport pathways to prevent the build-up of hydrostatic pressure that otherwise offsets lysosomal dynamics including vesiculation, tubulation and fission. Without undergoing rupture, we found that lysosomes incurring this pressure owing to defects in solute efflux, are unable to retain luminal Na+, which collapses its gradient with the cytosol. This cation 'leak' is mediated by pressure-sensitive channels resident to lysosomes and leads to the inhibition of mTORC1, which is normally activated by Na+-coupled amino acid transporters driven by the Na+ gradient. As a consequence, the transcription factors TFEB/TFE3 are made active in macrophages with distended lysosomes. In addition to their role in lysosomal biogenesis, TFEB/TFE3 activation causes the release of MCP-1/CCL2. In catabolically stressed tissues, defects in efflux of solutes from the endocytic pathway leads to increased monocyte recruitment. Here we propose that macrophages respond to a pressure-sensing pathway on lysosomes to orchestrate lysosomal biogenesis as well as myeloid cell recruitment.

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