Biomechanical Control of Lysosomal Secretion Via the VAMP7 Hub: A Tug-of-War Mechanism Between VARP and LRRK1

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 found that cells deficient in the secretory lysosome v-SNARE VAMP7 were impaired in adapting to substrate rigidity. Conversely VAMP7-mediated secretion was stimulated by more rigid substrate and this regulation depended on the Longin domain of VAMP7. We further found that the Longin domain bound the kinase and retrograde trafficking adaptor LRRK1 and LRRK1 negatively regulated VAMP7-mediated exocytosis. Conversely, VARP, a VAMP7- and kinesin 1- interacting protein, further controlled the availability for secretion of peripheral VAMP7 vesicles and response of cells to mechanical constraints. We propose a mechanism whereby biomechanical constraints regulate VAMP7-dependent lysosomal secretion via LRRK1 and VARP tug-of-war control of the peripheral readily-releasable pool of secretory lysosomes.