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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: 33.12). 01/2012; 148(1-2):201-12. DOI: 10.1016/j.cell.2011.10.051
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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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    • "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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    • "A recent systematic study in P. bergheiinfected erythrocytes identified 13 previously unrecognized PEXEL/HT proteins and PNEPs (Pasini et al., 2013), suggesting that other, and perhaps all, Plasmodium species export a large and diverse set of proteins to remodel the erythrocyte. The current data from asexual blood-stage parasites indicate that the PEXEL/HT-motif is cleaved by plasmepsin V in the parasite endoplasmic reticulum (Boddey et al., 2010; Russo et al., 2010), where the PEXEL/HTcontaining proteins are proposed to be recruited by binding to phosphatidylinositol 3-phosphate (PI3P) (Bhattacharjee et al., 2012). Identification of cleaved, N-acetylated peptides from PEXEL/HT proteins in stage I gametocytes indicates that this machinery is also active in the endoplasmic reticulum of gametocytes, an observation further supported by the fact that plasmepsin V is readily detectable in the proteomes of all asexual and sexual blood stages (Silvestrini et al., 2010). "
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