Abstract
Extracellular matrix (ECM) assembly and remodelling is critical during development and organ morphogenesis. Dysregulation of ECM is implicated in many pathogenic conditions, including cancer. The type II transmembrane serine protease matriptase and the serine protease prostasin are key factors in a proteolytic cascade that regulates epithelial ECM differentiation during development in vertebrates. Here, we show by rescue experiments that the Drosophila proteases Notopleural (Np) and Tracheal-prostasin (Tpr) are functional homologues of matriptase and prostasin, respectively. Np mediates morphogenesis and remodelling of apical ECM during tracheal system development and is essential for maintenance of the transepithelial barrier function. Both Np and Tpr degrade the zona pellucida-domain (ZP-domain) protein Dumpy, a component of the transient tracheal apical ECM. Furthermore, we demonstrate that Tpr zymogen and the ZP domain of the ECM protein Piopio are cleaved by Np and matriptase in vitro. Our data indicate that the evolutionarily conserved ZP domain, present in many ECM proteins of vertebrates and invertebrates, is a novel target of the conserved matriptase-prostasin proteolytic cascade.
Highlights
Epithelial development establishes the basis for normal body shape and organ function
We show that a central regulator of extracellular matrix (ECM) differentiation and epithelial development in vertebrates, the matriptase-prostasin proteolytic cascade (MPPC), is conserved and essential for both Drosophila
We initially identified the gene CG34350 in an RNA interference (RNAi) screen for genes required for gas filling of the tracheal tubes, a process referred to as liquid clearance (LC) [27]
Summary
Epithelial development establishes the basis for normal body shape and organ function. Sheets of epithelial cells separate different chemical milieus inside the body. They protect the body from the outside and organize into elaborate complex structures such as stratified epithelia and branched tubules [1,2]. Tissues mediate these diverse functions by controlling the paracellular flow of water-soluble molecules and by generating an extracellular matrix (ECM) that is critical both for organ shape and function as well as protecting organs from their surroundings [3,4]. Matriptase activates the membrane-anchored serine protease prostasin by proteolytic cleavage, which is required to initiate a cascade in epithelial development (for review see [8]). The matriptase-prostasin cascade appears to be fundamental for normal epithelial development, and its deregulation is linked to many pathogenic conditions
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