Transcriptional Activation of Lysosomal Exocytosis Promotes Cellular Clearance

TLDR

Lysosomes are organelles involved in degradation and recycling, and during Ca²⁺‑regulated exocytosis they fuse with the plasma membrane to secrete contents and repair the membrane. TFEB increases lysosome proximity to the plasma membrane and promotes fusion by elevating intracellular Ca²⁺ through activation of the lysosomal Ca²⁺ channel MCOLN1. TFEB‑driven lysosomal exocytosis rescues pathological storage, restores normal cellular morphology in vitro and in vivo in lysosomal storage diseases, and suggests a therapeutic strategy for disorders with intracellular storage.

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.