Autophagy–mediated plasma membrane removal promotes the formation of epithelial syncytia

Abstract

Epithelial wound healing in Drosophila involves the formation of multinucleate cells surrounding the wound. We show that autophagy, a cellular degradation process often deployed in stress responses, is required for the formation of a multinucleated syncytium during wound healing, and that autophagosomes that appear near the wound edge acquire plasma membrane markers. In addition, uncontrolled autophagy in the unwounded epidermis leads to the degradation of endo‐membranes and the lateral plasma membrane, while apical and basal membranes and epithelial barrier function remain intact. Proper functioning of TORC1 is needed to prevent destruction of the larval epidermis by autophagy, in a process that depends on phagophore initiation and expansion but does not require autophagosomes fusion with lysosomes. Autophagy induction can also affect other sub‐cellular membranes, as shown by its suppression of experimentally induced laminopathy‐like nuclear defects. Our findings reveal a function for TORC1‐mediated regulation of autophagy in maintaining membrane integrity and homeostasis in the epidermis and during wound healing.

Giant Multinucleated Cells in Aging and Senescence—An Abridgement

“…Autophagy is a common process in development, differentiation, and tissue remodeling and is activated during wound healing in Drosophila and other species [ 71 ]. Studies in Drosophila showed that autophagy can also have cytoprotective functions [ 72 ] and induces formation of multinucleated giant cells [ 73 ]. Drosophila larvae have elevated levels of autophagy in the epidermis, both during development and epidermal wound healing [ 73 ].…”

“…Studies in Drosophila showed that autophagy can also have cytoprotective functions [ 72 ] and induces formation of multinucleated giant cells [ 73 ]. Drosophila larvae have elevated levels of autophagy in the epidermis, both during development and epidermal wound healing [ 73 ]. Autophagy induces cell membrane breakdown, facilitating cell fusion and the formation of giant syncytial cells [ 73 ].…”

“…Drosophila larvae have elevated levels of autophagy in the epidermis, both during development and epidermal wound healing [ 73 ]. Autophagy induces cell membrane breakdown, facilitating cell fusion and the formation of giant syncytial cells [ 73 ]. Other studies showed that autophagy is necessary to form syncytiotrophoblast in the mammalian placenta and myoblast fusion [ 74 , 75 ].…”

Autophagy power expands: fuse those cells!

“…Kakanj et al set out to investigate whether autophagy could be involved in wound healing using a refined and powerful video microscopy set up with anaesthetized larvae triggered by single‐cell laser‐induced wounding (Kakanj et al , 2022). This allows highly stereotypic manipulation, and detailed observational and genetic analyses of wound healing dynamics that is completed within 2–3 h. Using fluorescently tagged Atg8a that label the autophagic membranes, they verified that autophagy markers were increased in cells surrounding the wound and peaked at about 120 min after injury, when wound closure is nearly complete.…”

“…The lysosomal degradation pathway of autophagy depends on a set of evolutionarily conserved autophagy-related molecules (ATGs) bestowed with the power to direct membrane trafficking and biology. In this issue of EMBO Journal, Kakanj P et al reveal a surprising role for the autophagy machinery in cell fusion (Kakanj et al, 2022). Autophagy is physiologically required for cell syncytium formation through dismantling the lateral plasma membrane during wound healing, and unchecked autophagy can drive cell fusion in epithelial tissues without compromising epithelial integrity.…”