The transmembrane protein Macroglobulin complement-related is essential for septate junction formation and epithelial barrier function inDrosophila

Abstract

Occluding cell-cell junctions in epithelia form physical barriers that separate different membrane domains, restrict paracellular diffusion and prevent pathogens from spreading across tissues. In invertebrates, these functions are provided by septate junctions (SJs), the functional equivalent of vertebrate tight junctions. How the diverse functions of SJs are integrated and modulated in a multiprotein complex is not clear, and many SJ components are still unknown. Here we report the identification of Macroglobulin complement-related (Mcr), a member of the conserved α-2-macroglobulin (α2M) complement protein family, as a novel SJ-associated protein in Drosophila. Whereas α2M complement proteins are generally known as secreted factors that bind to surfaces of pathogens and target them for phagocytic uptake, Mcr represents an unusual α2M protein with a predicted transmembrane domain. We show that Mcr protein localizes to lateral membranes of epithelial cells, where its distribution overlaps with SJs. Several SJ components are required for the correct localization of Mcr. Conversely, Mcr is required in a cellautonomous fashion for the correct membrane localization of SJ components, indicating that membrane-bound rather than secreted Mcr isoforms are involved in SJ formation. Finally, we show that loss of Mcr function leads to morphological, ultrastructural and epithelial barrier defects resembling mutants lacking SJ components. Our results, along with previous findings on the role of Mcr in phagocytosis, suggest that Mcr plays dual roles in epithelial barrier formation and innate immunity. Thus, Mcr represents a novel paradigm for investigating functional links between occluding junction formation and pathogen defense mechanisms.

Tsetse fly tolerance to T. brucei infection: transcriptome analysis of trypanosome-associated changes in the tsetse fly salivary gland

“…The strong upregulation of the different Teps (especially Tep2) in the salivary glands in the presence of the trypanosome infection suggests a possible role of this protein family in the interaction with the Tbb parasite population in the tissue. Moreover, the high similarity of the predicted Tep4 protein with the DmTep6-Mcr protein in Drosophila could indicate a similar role of this protein as described for Drosophila in the formation and maintenance of the septate junctions in the epithelial cell lining in the tsetse salivary glands [37, 38]. Indeed, the tight attachment of the trypanosome flagellum to this epithelial lining [39] in the infected glands could possibly cause damage to the septate junctions.…”

Thioester-Containing Protein-4 Regulates the <b><i>Drosophila</i></b> Immune Signaling and Function against the Pathogen <b><i>Photorhabdus</i></b>

“…TEP1-TEP4 proteins are constitutively expressed in plasmatocytes [1] whereas TEP6 has been shown to be a transmembrane protein that is required for septate junction formation [9] . Specifically, the Tep4 gene is expressed in both larval stages as well as in adult flies [1] .…”

Arthropod Innate Immune Systems and Vector-Borne Diseases

“…113,114 Mcr is also reported to function in hemocytic immune responses. Mcr is expressed in plasmatocytes.…”