title: Endoplasmic reticulum PI(3)P lipid binding targets malaria proteins to the host cell.
abstract: Hundreds of effector proteins of the human malaria parasite Plasmodium falciparum constitute a "secretome" carrying a host-targeting (HT) signal, which predicts their export from the intracellular pathogen into the surrounding erythrocyte. Cleavage of the HT signal by a parasite endoplasmic reticulum (ER) protease, plasmepsin V, is the proposed export mechanism. Here, we show that the HT signal facilitates export by recognition of the lipid phosphatidylinositol-3-phosphate (PI(3)P) in the ER, prior to and independent of protease action. Secretome HT signals, including those of major virulence determinants, bind PI(3)P with nanomolar affinity and amino acid specificities displayed by HT-mediated export. PI(3)P-enriched regions are detected within the parasite's ER and colocalize with endogenous HT signal on ER precursors, which also display high-affinity binding to PI(3)P. A related pathogenic oomycete's HT signal export is dependent on PI(3)P binding, without cleavage by plasmepsin V. Thus, PI(3)P in the ER functions in mechanisms of secretion and pathogenesis.
authors.affiliation: Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Souvik
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: Robert V
authors.initials: RV
authors.lastname: Stahelin
authors.forename: Kaye D
authors.initials: KD
authors.lastname: Speicher
authors.forename: David W
authors.initials: DW
authors.lastname: Speicher
authors.forename: Kasturi
authors.initials: K
authors.lastname: Haldar
mesh_terms: D000595:Amino Acid Sequence; D000953:Antigens, Protozoan / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology* / Q000473:pathology; D008969:Molecular Sequence Data; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000166:cytology / Q000378:metabolism*; D021382:Protein Sorting Signals; D021381:Protein Transport; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000953:Antigens, Protozoan; C514457:HRP-2 antigen, Plasmodium falciparum; D018129:Phosphatidylinositol Phosphates; D021382:Protein Sorting Signals; D015800:Protozoan Proteins; C055525:phosphatidylinositol 3-phosphate; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin