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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    • "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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    ABSTRACT: Orphan genes are protein coding genes that lack recognizable homologs in other organisms. These genes were reported to comprise a considerable fraction of coding regions in all sequenced genomes and thought to be allied with organism's lineage-specific traits. However, their evolutionary persistence and functional significance still remain elusive. Due to lack of homologs with the host genome and for their probable lineage-specific functional roles, orphan gene product of pathogenic protozoan might be considered as the possible therapeutic targets. L. major is an important parasitic protozoan of the genus Leishmania that is associated with the disease cutaneous leishmaniasis. Therefore, evolutionary and functional characterization of orphan genes in this organism may help in understanding the factors prevailing pathogen evolution and parasitic adaptation. In this study, we systematically identified orphan genes of L. major and employed several in-silico analyses for understanding their evolutionary and functional attributes. To trace the signatures of molecular evolution, we compared their evolutionary rate with non-orphan genes. In agreement with prior observations, here we noticed that orphan genes evolve at a higher rate as compared to non-orphan genes. Lower sequence conservation of orphan genes was previously attributed solely due to their younger gene age. However, here we observed that together with gene age, a number of genomic (like expression level, GC content, variation in codon usage) and proteomic factors (like protein length, intrinsic disorder content, hydropathicity) could independently modulate their evolutionary rate. We considered the interplay of all these factors and analyzed their relative contribution on protein evolutionary rate by regression analysis. On the functional level, we observed that orphan genes are associated with regulatory, growth factor and transport related processes. Moreover, these genes were found to be enriched with various types of interaction and trafficking motifs, implying their possible involvement in host-parasite interactions. Thus, our comprehensive analysis of L. major orphan genes provided evidence for their extensive roles in host-pathogen interactions and virulence. Copyright © 2015. Published by Elsevier B.V.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 04/2015; 32. DOI:10.1016/j.meegid.2015.03.031 · 3.02 Impact Factor
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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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    • "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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