Koussis Konstantinos, Goulielmaki Evi, Chalari Anna, Withers-Martinez Chrislaine, Siden-Kiamos Inga, Matuschewski Kai, Loukeris Thanasis G
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.
Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany.
PLoS One. 2017 Jan 20;12(1):e0170260. doi: 10.1371/journal.pone.0170260. eCollection 2017.
Site-2 proteases (S2P) belong to the M50 family of metalloproteases, which typically perform essential roles by mediating activation of membrane-bound transcription factors through regulated intramembrane proteolysis (RIP). Protease-dependent liberation of dormant transcription factors triggers diverse cellular responses, such as sterol regulation, Notch signalling and the unfolded protein response. Plasmodium parasites rely on regulated proteolysis for controlling essential pathways throughout the life cycle. In this study we examine the Plasmodium-encoded S2P in a murine malaria model and show that it is expressed in all stages of Plasmodium development. Localisation studies by endogenous gene tagging revealed that in all invasive stages the protein is in close proximity to the nucleus. Ablation of PbS2P by reverse genetics leads to reduced growth rates during liver and blood infection and, hence, virulence attenuation. Strikingly, absence of PbS2P was compatible with parasite life cycle progression in the mosquito and mammalian hosts under physiological conditions, suggesting redundant or dispensable roles in vivo.
2型位点蛋白酶（S2P）属于金属蛋白酶的M50家族，其通常通过受调控的膜内蛋白水解作用（RIP）介导膜结合转录因子的激活，从而发挥重要作用。蛋白酶依赖性的休眠转录因子释放引发多种细胞反应，如固醇调节、Notch信号传导和未折叠蛋白反应。疟原虫在整个生命周期中依靠受调控的蛋白水解作用来控制关键途径。在本研究中，我们在鼠疟模型中研究了疟原虫编码的S2P，并表明它在疟原虫发育的所有阶段均有表达。通过内源性基因标记进行的定位研究表明，在所有侵入阶段，该蛋白都与细胞核紧密相邻。通过反向遗传学方法敲除PbS2P会导致肝脏和血液感染期间生长速率降低，进而毒力减弱。引人注目的是，在生理条件下，缺乏PbS2P与疟原虫在蚊子和哺乳动物宿主中的生命周期进展是相容的，这表明其在体内具有冗余或非必需的作用。
