title: Transcriptional activation of lysosomal exocytosis promotes cellular clearance.
abstract: Lysosomes are cellular organelles primarily involved in degradation and recycling processes. During lysosomal exocytosis, a Ca²⁺-regulated process, lysosomes are docked to the cell surface and fuse with the plasma membrane (PM), emptying their content outside the cell. This process has an important role in secretion and PM repair. Here we show that the transcription factor EB (TFEB) regulates lysosomal exocytosis. TFEB increases the pool of lysosomes in the proximity of the PM and promotes their fusion with PM by raising intracellular Ca²⁺ levels through the activation of the lysosomal Ca²⁺ channel MCOLN1. Induction of lysosomal exocytosis by TFEB overexpression rescued pathologic storage and restored normal cellular morphology both in vitro and in vivo in lysosomal storage diseases (LSDs). Our data indicate that lysosomal exocytosis may directly modulate cellular clearance and suggest an alternative therapeutic strategy for disorders associated with intracellular storage.
authors: Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131 Naples, Italy.
authors: Diego L
authors: DL
authors: Medina
authors: Alessandro
authors: A
authors: Fraldi
authors: Valentina
authors: V
authors: Bouche
authors: Fabio
authors: F
authors: Annunziata
authors: Gelsomina
authors: G
authors: Mansueto
authors: Carmine
authors: C
authors: Spampanato
authors: Claudia
authors: C
authors: Puri
authors: Antonella
authors: A
authors: Pignata
authors: Jose A
authors: JA
authors: Martina
authors: Marco
authors: M
authors: Sardiello
authors: Michela
authors: M
authors: Palmieri
authors: Roman
authors: R
authors: Polishchuk
authors: Rosa
authors: R
authors: Puertollano
authors: Andrea
authors: A
authors: Ballabio
mesh_terms: D000818:Animals; D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005089:Exocytosis / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D008561:Membrane Fusion; D051379:Mice; D052517:Multiple Sulfatase Deficiency Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050053:TRPM Cation Channels / Q000235:genetics*; D015533:Transcriptional Activation; D050051:Transient Receptor Potential Channels; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C416674:MCOLN1 protein, human; C064972:TFEB protein, human; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels; D002118:Calcium