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Lookup NU author(s): Professor Viktor KorolchukORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.A robust and efficient cellular response to lysosomal membrane damage prevents leakage from the lysosome lumen into the cytoplasm. This response is understood to happen through either lysosomal membrane repair or lysophagy. Here we report exocytosis as a third response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired. We show that Connexin43 (Cx43), a protein canonically associated with gap junctions, is recruited from the plasma membrane to damaged lysosomes, promoting their secretion and accelerating cell recovery. The effects of Cx43 on lysosome exocytosis are mediated by a reorganization of the actin cytoskeleton that increases plasma membrane fluidity and decreases cell stiffness. Furthermore, we demonstrate that Cx43 interacts with the actin nucleator Arp2, the activity of which was shown to be necessary for Cx43-mediated actin rearrangement and lysosomal exocytosis following damage. These results define a novel mechanism of lysosomal quality control whereby Cx43-mediated actin remodelling potentiates the secretion of damaged lysosomes.
Author(s): Domingues N, Catarino S, Cristovao B, Rodrigues L, Carvalho FA, Sarmento MJ, Zuzarte M, Almeida J, Ribeiro-Rodrigues T, Correia-Rodrigues A, Fernandes F, Rodrigues-Santos P, Aasen T, Santos NC, Korolchuk VI, Goncalves T, Milosevic I, Raimundo N, Girao H
Publication type: Article
Publication status: Published
Journal: EMBO Journal
Year: 2024
Volume: 43
Issue: 17
Pages: 3627-3649
Print publication date: 01/09/2024
Online publication date: 23/07/2024
Acceptance date: 09/07/2024
Date deposited: 17/09/2024
ISSN (electronic): 1460-2075
Publisher: EMBO Press
URL: https://doi.org/10.1038/s44318-024-00177-3
DOI: 10.1038/s44318-024-00177-3
Data Access Statement: This study includes no data deposited in external repositories. The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44318-024-00177-3.
PubMed id: 39044100
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