Biomechanical Control of Lysosomal Secretion Via the VAMP7 Hub: A Tug-of-War between VARP and LRRK1
Guan Wang,
Sébastien Nola,
Simone Bovio,
Philippe Bun,
Maïté Coppey-Moisan,
Frank Lafont,
Thierry Galli
Affiliations
Guan Wang
Membrane Traffic in Health & Disease, Institut Jacques Monod, CNRS UMR7592, INSERM U950, Sorbonne Paris-Cité, Université Paris Diderot, Paris 75205, France; Membrane Traffic in Healthy & Diseased Brain, Center of Psychiatry and Neurosciences, INSERM U894, Sorbonne Paris-Cité, Université Paris Descartes, 102-108 rue de la Santé, Paris 75014, France
Sébastien Nola
Membrane Traffic in Health & Disease, Institut Jacques Monod, CNRS UMR7592, INSERM U950, Sorbonne Paris-Cité, Université Paris Diderot, Paris 75205, France; Membrane Traffic in Healthy & Diseased Brain, Center of Psychiatry and Neurosciences, INSERM U894, Sorbonne Paris-Cité, Université Paris Descartes, 102-108 rue de la Santé, Paris 75014, France
Simone Bovio
Cellular Microbiology and Physics of Infection Group, Center for Infection and Immunity of Lille, CNRS UMR 8204, INSERM U1019, Institut Pasteur de Lille, Centre Hospitalier Régional de Lille, Université de Lille, Lille, France
Philippe Bun
NeurImag Tech Core Facility, Center of Psychiatry and Neurosciences, INSERM U894, Sorbonne Paris-Cité, Université Paris Descartes, Paris 75014, France
Maïté Coppey-Moisan
Mechanotransduction: from Cell Surface to Nucleus, Institut Jacques Monod, CNRS UMR7592, Sorbonne Paris-Cité, Université Paris-Diderot, Paris, France
Frank Lafont
Cellular Microbiology and Physics of Infection Group, Center for Infection and Immunity of Lille, CNRS UMR 8204, INSERM U1019, Institut Pasteur de Lille, Centre Hospitalier Régional de Lille, Université de Lille, Lille, France
Thierry Galli
Membrane Traffic in Health & Disease, Institut Jacques Monod, CNRS UMR7592, INSERM U950, Sorbonne Paris-Cité, Université Paris Diderot, Paris 75205, France; Membrane Traffic in Healthy & Diseased Brain, Center of Psychiatry and Neurosciences, INSERM U894, Sorbonne Paris-Cité, Université Paris Descartes, 102-108 rue de la Santé, Paris 75014, France; Corresponding author
Summary: The rigidity of the cell environment can vary tremendously between tissues and in pathological conditions. How this property may affect intracellular membrane dynamics is still largely unknown. Here, using atomic force microscopy, we show that cells deficient in the secretory lysosome v-SNARE VAMP7 are impaired in adaptation to substrate rigidity. Conversely, VAMP7-mediated secretion is stimulated by more rigid substrate and this regulation depends on the Longin domain of VAMP7. We further find that the Longin domain binds the kinase and retrograde trafficking adaptor LRRK1 and that LRRK1 negatively regulates VAMP7-mediated exocytosis. Conversely, VARP, a VAMP7- and kinesin 1-interacting protein, further controls the availability for secretion of peripheral VAMP7 vesicles and response of cells to mechanical constraints. LRRK1 and VARP interact with VAMP7 in a competitive manner. We propose a mechanism whereby biomechanical constraints regulate VAMP7-dependent lysosomal secretion via LRRK1 and VARP tug-of-war control of the peripheral pool of secretory lysosomes. : Cell Biology; Functional Aspects of Cell Biology; Biomechanics Subject Areas: Cell Biology, Functional Aspects of Cell Biology, Biomechanics
