Research Group Molecular Organogenesis, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.
Research Group Mass Spectrometry, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.
PLoS Genet. 2019 Jan 2;15(1):e1007882. doi: 10.1371/journal.pgen.1007882. eCollection 2019 Jan.
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.
细胞外基质（ECM）的组装和重塑在发育和器官形态发生过程中至关重要。ECM 的失调与许多病理状况有关，包括癌症。II 型跨膜丝氨酸蛋白酶 matriptase 和丝氨酸蛋白酶 prostasin 是一个蛋白水解级联反应中的关键因素，该级联反应调节脊椎动物发育过程中上皮细胞 ECM 的分化。在这里，我们通过挽救实验表明，果蝇蛋白酶 Notopleural (Np) 和 Tracheal-prostasin (Tpr) 分别是 matriptase 和 prostasin 的功能同源物。Np 介导气管系统发育过程中顶细胞外基质的形态发生和重塑，对于维持上皮细胞的跨上皮屏障功能是必需的。Np 和 Tpr 均可降解透明带域（ZP 域）蛋白 Dumpy，该蛋白是短暂气管顶细胞外基质的一个组成部分。此外，我们证明 Np 和 matriptase 在体外可切割 Tpr 酶原和 ECM 蛋白 Piopio 的 ZP 结构域。我们的数据表明，存在于脊椎动物和无脊椎动物许多 ECM 蛋白中的进化上保守的 ZP 结构域是保守的 matriptase-prostasin 蛋白水解级联反应的一个新靶点。
