title: Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis.
abstract: Previously we described the identification of a Plasmodium falciparum signal peptide peptidase (PfSPP) functioning at the blood stage of malaria infection. Our studies also demonstrated that mammalian SPP inhibitors prevent malaria parasite growth at the late-ring/early trophozoite stage of intra-erythrocytic development. Consistent with its role in development, we tested the hypothesis that PfSPP functions at the endoplasmic reticulum of P.falciparum where it cleaves membrane-bound signal peptides generated following the enzyme activity of signal peptidase. The localization of PfSPP to the endoplasmic reticulum was confirmed by immunofluorescence microscopy and immunogold electron microscopy. Biochemical analysis indicated the existence of monomer and dimer forms of PfSPP in the parasite lysate. A comprehensive bioinformatics screen identified several candidate PfSPP substrates in the parasite genome. Using an established transfection based in vivo luminescence assay, malaria heat shock protein 101 (HSP101) was identified as a substrate of PfSPP, and partial inhibition of PfSPP correlated with the emergence of gametocytes. This finding unveils the first known substrate of PfSPP, and provides new perspectives for the function of intra-membrane proteolysis at the erythrocyte stage of malaria parasite life cycle.
authors.affiliation: Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Baldwin
authors.affiliation: Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, United States.
authors.forename: Crystal
authors.initials: C
authors.lastname: Russo
authors.affiliation: Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, United States.
authors.forename: Xuerong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, United States; Sackler School of Graduate Biomedical Sciences, Programs in Physiology, Pharmacology, and Microbiology, Tufts University School of Medicine, Boston, MA 02111, United States. Electronic address: athar.chishti@tufts.edu.
authors.forename: Athar H
authors.initials: AH
authors.lastname: Chishti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D005854:Germ Cells / Q000166:cytology*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000201:enzymology*; D059748:Proteolysis
chemical_list: D006360:Heat-Shock Proteins; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase
keywords: ER stress; Endoplasmic reticulum; Intramembrane cleaving protease; Malaria; Signal peptide peptidase