The Drosophila Mcr protein is a member of the thioester protein (TEP) family of proteins, which includes key regulators of innate immunity. Mcr is an unusual member of this family, possessing a putative transmembrane domain and lacking a key residue in the thioester motif. It has, nevertheless, been shown to be involved in phagocytic uptake in cultured Drosophila cells, although its putative immune functions have not been assessed in vivo. Two papers, from Stefan Luschnig and colleagues (p. 899) and Robert Ward and colleagues (p. 889), now identify Mcr as a new component of septate junctions (SJs), the invertebrate equivalent of tight junctions that form the paracellular barrier in epithelia.

Both studies identify lethal EMS mutations in Mcr in independent genetic screens, finding mutant phenotypes typical of SJ components. Consistent with a putative role in SJ formation, the protein colocalises with other SJ proteins at the lateral membrane. They further find that Mcr localisation is dependent on core SJ components and that, conversely, SJ proteins are mislocalised in Mcr mutants. At the morphological and ultrastructural level, SJs are disrupted in the absence of Mcr, and functional assays demonstrate that Mcr is required to form an effective paracellular barrier. As well as identifying a new SJ protein essential for barrier integrity, these two studies suggest an intriguing link between SJs and innate immunity. The epithelial barrier represents the first line of defence against pathogen invasion, and Drosophila haemocytes are known to undergo an epithelialisation-like process when encapsulating pathogens in the haemolymph. The identification of Mcr as a protein involved in both SJ formation and innate immunity now provides a molecular connection, and opens up new avenues for investigating potential functional links, between these two seemingly disparate processes.