Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling

Author:

Domingues Neuza,Catarino SteveORCID,Cristóvão Beatriz,Rodrigues LisaORCID,Carvalho Filomena AORCID,Sarmento Maria JoãoORCID,Zuzarte Mónica,Almeida JaniORCID,Ribeiro-Rodrigues TeresaORCID,Correia-Rodrigues ÂniaORCID,Fernandes Fábio,Rodrigues-Santos PauloORCID,Aasen TrondORCID,Santos Nuno C,Korolchuk Viktor I,Gonçalves TeresaORCID,Milosevic Ira,Raimundo NunoORCID,Girão HenriqueORCID

Abstract

AbstractA 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.

Funder

MEC | Fundação para a Ciência e a Tecnologia

'la Caixa' Foundation

EC | Horizon 2020 Framework Programme

EC | European Regional Development Fund

John Black Charitable Foundation

Wellcome Trust

Publisher

Springer Science and Business Media LLC

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