Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling

Abstract

Actin-remodelling; Connexin43; Lysosomal damage

Remodelación de actina; Conexina43; Daño lisosomal

Remodelació d'actina; Connexina43; Dany lisosomal

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.

This work was supported by the European Regional Development Fund (ERDF) through the Operational Program for Competitiveness Factors (COMPETE) under the projects: PPBI-POCI-01-0145-FEDER-022122, UIDB/04539/2020, UIDP/04539/2020, project FCT-PTDC/MED-NEU/8030/2020, FCT-2022.09311, ‘la Caixa’ Foundation/HR22-00854, John Black Charitable Foundation and Wellcome Trust Award in Science/224361/Z/21/Z, Horizon 2020 grant 857524, and the Comissão de Coordenação e Desenvolvimento Regional do Centro - CCDRC through the Centro2020 Programme. This work was partially supported by the H2020 Twinning project RESETageing (GA 952266).