Crossing the Vacuolar Rubicon: Structural Insights into Effector Protein Trafficking in Apicomplexan Parasites

Abstract

Apicomplexans form a large phylum of parasitic protozoa, including the genera Plasmodium, Toxoplasma, and Cryptosporidium, the causative agents of malaria, toxoplasmosis, and cryptosporidiosis, respectively. They cause diseases not only in humans but also in animals, with dramatic consequences in agriculture. Most apicomplexans are vacuole-dwelling and obligate intracellular parasites; as they invade the host cell, they become encased in a parasitophorous vacuole (PV) derived from the host cellular membrane. This creates a parasite–host interface that acts as a protective barrier but also constitutes an obstacle through which the pathogen must import nutrients, eliminate wastes, and eventually break free upon egress. Completion of the parasitic life cycle requires intense remodeling of the infected host cell. Host cell subversion is mediated by a subset of essential effector parasitic proteins and virulence factors actively trafficked across the PV membrane. In the malaria parasite Plasmodium, a unique and highly specialized ATP-driven vacuolar secretion system, the Plasmodium translocon of exported proteins (PTEX), transports effector proteins across the vacuolar membrane. Its core is composed of the three essential proteins EXP2, PTEX150, and HSP101, and is supplemented by the two auxiliary proteins TRX2 and PTEX88. Many but not all secreted malarial effector proteins contain a vacuolar trafficking signal or Plasmodium export element (PEXEL) that requires processing by an endoplasmic reticulum protease, plasmepsin V, for proper export. Because vacuolar parasitic protein export is essential to parasite survival and virulence, this pathway is a promising target for the development of novel antimalarial therapeutics. This review summarizes the current state of structural and mechanistic knowledge on the Plasmodium parasitic vacuolar secretion and effector trafficking pathway, describing its most salient features and discussing the existing differences and commonalities with the vacuolar effector translocation MYR machinery recently described in Toxoplasma and other apicomplexans of significance to medical and veterinary sciences.

Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

“…[137][138][139][140][141][142][143][144][145][146][147][148][149][150] that binds to EBH domains in end-binding proteins involved in microtubule transport [64], and a tyrosine-based YXXØ sorting signal (aa. [75][76][77][78] for interaction with the µ-subunit of adaptor protein complex [65] and a PEXEL-like motif [66]. The DDE region displayed the most consistent pattern of conserved ELMs among the betaretroviral INs.…”

PV1 Protein from Plasmodium falciparum Exhibits Chaperone-Like Functions and Cooperates with Hsp100s

“…Each AAA+ module binds and hydrolyses ATP and causes structural changes required for protein disaggregation [ 35 , 36 , 37 , 38 , 39 ]. PfHSP101 nucleotide binding domains (NBDs) share approximately 40% and 39% amino acid sequence identity with E. coli ClpB and yeast Hsp104, respectively [ 40 ]. HSP101 is exported PV space by the ER signal sequence and assembles with EXP2 and PTEX150 to form PTEX.…”

Unique Endomembrane Systems and Virulence in Pathogenic Protozoa

“…Thus, exported proteins destined for the erythrocyte also need to be translocated across the PVM after their arrival to the parasitophorous vacuole [ 132 , 154 ]. This translocation is accomplished by a large membrane complex called the Plasmodium translocon of exported proteins (PTEX) [ 154 , 155 ]. The three major proteins making up this complex are HSP101, PTEX150, and EXP2.…”