Cx43 promotes exocytosis of damaged lysosomes through actin remodelling

Abstract

Abstract A robust cellular response to lysosomal membrane damage is essential to prevent lysosomal content leakage to the cytoplasm and subsequent activation of cell death pathways. Here we report exocytosis as an important response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired. Our data reveal that Connexin43 (Cx43), a protein canonically associated with gap junctions, is recruited to damaged lysosomes to promote their secretion, thereby accelerating cell recovery. The exocytotic effects were found to be dependent on actin reorganization: Cx43 expression was associated with actin network remodelling, increased plasma membrane fluidity and decreased 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 identify a novel mechanism of lysosomal quality control whereby Cx43-mediated actin remodelling potentiates the secretion of damaged lysosomes.