title: Targeted Deletion of a Plasmodium Site-2 Protease Impairs Life Cycle Progression in the Mammalian Host.
abstract: 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.
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.|Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany.|Malaria Biochemistry Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Konstantinos
authors.identifier: http://orcid.org/0000-0002-6737-8724
authors.initials: K
authors.lastname: Koussis
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.
authors.forename: Evi
authors.initials: E
authors.lastname: Goulielmaki
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.|Department of Biology, University of Crete, Heraklion, Greece.
authors.forename: Anna
authors.initials: A
authors.lastname: Chalari
authors.affiliation: Malaria Biochemistry Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Chrislaine
authors.initials: C
authors.lastname: Withers-Martinez
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.
authors.forename: Inga
authors.initials: I
authors.lastname: Siden-Kiamos
authors.affiliation: Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany.|Institute of Biology, Humboldt University, Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.
authors.forename: Thanasis G
authors.initials: TG
authors.lastname: Loukeris
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000469:parasitology; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000737:chemistry / Q000235:genetics*; D010961:Plasmodium / Q000201:enzymology* / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D010447:Peptide Hydrolases