Transcriptional Activation of Lysosomal Exocytosis Promotes Cellular Clearance

By Diego L. Medina, A. Fraldi, V. Bouché, Fabio Annunziata, G. Mansueto, C. Spampanato, C. Puri, A. Pignata, J. Martina, Marco Sardiello and 4 more. Developmental Cell, 2011

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Summary 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.

Subfields: Cell Biology, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/8d03ca3cfdd802ab2f3e8b9ffcbd54e89686b28f

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Citations in the corpus

Lysosomal calcium signaling regulates autophagy via calcineurin and TFEB (2015, methodology): “…HSS108410-3, HSS1830463, HSS108411-3) or non-targeting siRNAs (Thermo, D-001810-10-05), by direct or reverse transfection, using LipofectamineRNAiMAX reagent (Invitrogen) according to the protocol from the manufacturer. siRNA-transfected cells were collected after 72 h, if not otherwise stated.”
MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB (2012, background): “TFEB overexpression induces increased number of autophagosomes and autophagic flux, generation of new lysosomes, and leads to clearance of storage material in several lysosomal storage disorders (LSDs) by promoting lysosomal secretion.(12,14) In this study we show that MTORC1 drives expression of au”
TFEB at a glance (2016, background): “…have been shown to be beneficial in reducing substrate accumulation; such overexpression also improved overall autophagy and lysosomal function, and ameliorated the severity of cellular and tissue phenotypes (Medina et al., 2011; Rega et al., 2016; Song et al., 2013; Spampanato et al., 2013).”
The lysosome: from waste bag to potential therapeutic target. (2013, background): “TFEB overexpression has been shown to reverse pathologic lysosomal storage by stimulating lysosomal exocytosis (Medina et al., 2011).”
Handbook of ion channels (2015, background): “In addition, modulation of TFEB-dependent autophagic pathway might prove promising for ML4 and other LSDs (66).”
Membrane Lipid Composition: Effect on Membrane and Organelle Structure, Function and Compartmentalization and Therapeutic Avenues (2019, background): “TFEB effect first enhances lysosomal exocytosis [91], second promotes the degradation of autophagic substrates and third helps the clearance of lipid droplets and of mitochondria [92–94].”
The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. (2012, neutral): “…2008 Gene therapy (GT) Nucleus + + In progress Gritti, 2011; Tomanin et al., 2012 Stop codon read-through Nucleus + Brooks et al., 2006 Calcium modulation therapy (CMT) ER + + Lloyd-Evans et al., 2008 Enhanced exocytosis therapy (ExT) Exosome + Strauss et al., 2010; Medina et al., 2011”
Lysosomal Physiology (2015, background): “Mucolipin synthetic agonist 1 treatment resulted in the localization of Lamp1 on the plasma membrane (red ) in nonpermeabilized wild-type (WT), but not TRPML1 (mucolipin TRP channel 1) knockout (KO), macrophages.”
A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB (2012, background): “Finally, as TFEB overexpression was able to promote substrate clearance and to rescue cellular vacuolization in LSDs (Medina et al , 2011), the identiﬁcation of a lysosome-based, mTOR-mediated, mechanism that regulates TFEB activity offers a new tool to promote cellular clearance in health and…”