Conserved function of the matriptase-prostasin proteolytic cascade during epithelial morphogenesis

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.

Control of tissue morphogenesis by the HOX gene Ultrabithorax

“…Np appears to be the key missing protease, as silencing of both Sb and Np by RNAi prevents formation of a normal adult wing, instead generating a reduced structure that has failed to fully expand or elongate during either early or late stages of metamorphosis (Figs 2 and 3). Indeed, it was recently shown that Np is necessary to degrade Dumpy in the Drosophila embryo (Drees et al, 2019).…”

Form and function of the apical extracellular matrix: new insights from Caenorhabditis elegans, Drosophila melanogaster, and the vertebrate inner ear

“…As well as having defective epidermal barrier function, Tyn mutants display aberrant taenidial channels, likely impairing endocytic clearance of luminal aECMs and resulting in defective gas filling of the trachea 29 . The matriptase-related protease Notopleural (Np) is also essential for liquid clearance and gas filling of the tracheal tubes 45 . Np mutant embryos have normal chitin deposition and clearance but develop an unstructured aECM lacking taenidial folds.…”

Membrane-anchored serine proteases as regulators of epithelial function

“…Both diseases present with skin defects that include mild to moderate ichthyosis, indicative of compromised epidermal barrier function (Table 1). Finally, the matriptase and prostasin homologs, Notopleural and Tracheal-prostasin, are essential for the establishment of airway barrier function and embryonic survival in Drosophila (see below) [24]. Consistent with the in vivo studies, inhibition or elimination of matriptase activity results in decreased ability of cultured intestinal and kidney epithelial cells to establish and maintain fully functional barriers [25,26].…”

“…Drosophila Notopleural and Trp, which encode proteases homologous to, respectively, human matriptase and prostasin, have recently been shown to be essential for degradation of intraluminal chitin in the trachea of Drosophila, leading to a defect in barrier function, impaired tracheal liquid clearance and death before hatching [24]. Notopleural mutant and Trp knockdown embryos show defects in cleavage of apical ECM ZP protein Dumpy, which plays an important role in attachment of the epithelium to the exoskeleton at later stages of Drosophila development [85].…”