Article

Endoplasmic Reticulum PI(3)P Lipid Binding Targets Malaria Proteins to the Host Cell

Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA.
Cell (Impact Factor: 32.24). 01/2012; 148(1-2):201-12. DOI: 10.1016/j.cell.2011.10.051
Source: PubMed

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.

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Available from: Kasturi Haldar, Dec 24, 2014
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    • "Based on the P. falciparum parasite genome, 463 proteins are predicted as PEXEL exportomes[17]. The malaria parasite employs the PEXEL motif to export proteins into the host erythrocyte by binding to phosphatidylinositol-3-phosphate (PI3P) in the inner leaflet of the ER membrane[18]and the PEXEL motif is subsequently cleaved by the ER-resident aspartic protease plasmepsin V (PMV)[19,20]. This enzyme recognizes the PEXEL motif and cleaves it after Leu, generating a –X-E/Q/D which is then acetylated by an unidentified enzyme, leading to the formation of Ac-X-E/Q/D19202122. "
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    Full-text · Article · Jan 2016 · Molecular and Biochemical Parasitology
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    • "We investigated for host-cell targeting motifs RXLXE/D/Q (where X is a neutral or a hydrophobic amino acid residue) that were previously reported for their activity to export Plasmodium falciparum proteins from the intracellular parasites (Bhattacharjee et al., 2012) to the surrounding erythrocytes. We also searched for the presence of consensus sequences XBBXBX, XBBBXXBX and XBBBXXBBBXXBBX (where X is a neutral or hydrophobic amino acid residue and B is a basic amino acid residue ) which were implicated in hairpin binding (de Castro Cortes et al., 2012). "
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    Full-text · Article · Apr 2015 · Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases
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    • "It is not clear whether the early endosome, which in mammalian cells is decorated with the lipid PI3P and Rab5, exists as a discrete compartment in P. falciparum. PI3P has been localized to the food vacuole, the apicoplast and the luminal face of the ER [68], [69], none of which appears to represent a canonical early endosome. "
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    Full-text · Article · Feb 2014 · PLoS ONE
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