Future wing of a fruit fly pupa, showing individual cells. Shown in grey are wildtype cells with intact Retromer activity, which is missing in areas of the tissue lacking grey signal (visible in the centre of the image). The wildtype cells that have Retromer function have successfully delivered Neurexin IV (a septate junction protein, orange) to the membrane of the cell (visible at the top and bottom of the image); while the cells that lack Retromer have failed to do so. Image credit: Hendrik Pannen (CC BY 4.0)
Proteins are large molecules responsible for a variety of activities that cells needs to perform to survive; from respiration to copying DNA before cells divide. To perform these roles proteins need to be transported to the correct cell compartment, or to the cell membrane. This protein trafficking depends on the endosomal system, a set of membrane compartments that can travel within the cell and act as a protein sorting hub. This system needs its own proteins to work properly. In particular, there are two sets of proteins that are crucial for the endosomal systems activity: a group of proteins known as the ESCRT (endosomal sorting complex required for transport) machinery and a complex called retromer. The retromer complex regulates recycling of receptor proteins so they can be reused, while the ESCRT machinery mediates degradation of proteins that the cell does not require anymore. In the epithelia of fruit fly larvae – the tissues that form layers of cells, usually covering an organ but also making structures like wings – defects in ESCRT activity lead to a loss of tissue integrity.
This loss of tissue integrity suggests that the endosomal system might be involved in transporting proteins that form cellular junctions, the multiprotein complexes that establish contacts between cells or between a cell and the extracellular space. In arthropods such as the fruit fly, the adherens junction and the septate junction are two types of cellular junctions important for the integrity of epithelia integrity. Adherens junctions allow cells to adhere to each other, while septate junctions stop nutrient molecules, ions and water from leaking into the tissue. The role of the endosomal system in trafficking the proteins that form septate junctions remains a mystery.
To better understand the role of the endosomal system in regulating cell junctions and tissue integrity, Pannen et al. blocked the activity of either the ESCRT or retromer in wing imaginal discs – the future wings – of fruit fly larvae. Pannen et al. then analyzed the effects of these endosomal defects on cellular junctions using an imaging technique called transmission electron microscopy. The results showed that both ESCRT and retromer activities are necessary for the correct delivery of septate junction components to the cell membrane. However, neither retromer nor ESCRT were required for the delivery of adherens junction proteins.
These findings shed light on how retromer and the ESCRT machinery are involved in the epithelial tissue integrity of fruit fly larvae through their effects on cell junctions. Humans have their own versions of the ESCRT, retromer, and cell junction proteins, all of which are very similar to their fly counterparts. Since defects in the human versions of these proteins have been associated with a variety of diseases, from infections to cancer, these results may have implications for research into treating those diseases.
