Role of Plasmodium falciparum Protein GEXP07 in Maurer's Cleft Morphology, Knob Architecture, and P. falciparum EMP1 Trafficking.

Abstract

The malaria parasite Plasmodium falciparum traffics the virulence protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of infected red blood cells (RBCs) via membranous organelles, known as the Maurer's clefts. We developed a method for efficient enrichment of Maurer's clefts and profiled the protein composition of this trafficking organelle. We identified 13 previously uncharacterized or poorly characterized Maurer's cleft proteins. We generated transfectants expressing green fluorescent protein (GFP) fusions of 7 proteins and confirmed their Maurer's cleft location. Using co-immunoprecipitation and mass spectrometry, we generated an interaction map of proteins at the Maurer's clefts. We identified two key clusters that may function in the loading and unloading of PfEMP1 into and out of the Maurer's clefts. We focus on a putative PfEMP1 loading complex that includes the protein GEXP07/CX3CL1-binding protein 2 (CBP2). Disruption of GEXP07 causes Maurer's cleft fragmentation, aberrant knobs, ablation of PfEMP1 surface expression, and loss of the PfEMP1-mediated adhesion. ΔGEXP07 parasites have a growth advantage compared to wild-type parasites, and the infected RBCs are more deformable and more osmotically fragile.IMPORTANCE The trafficking of the virulence antigen PfEMP1 and its presentation at the knob structures at the surface of parasite-infected RBCs are central to severe adhesion-related pathologies such as cerebral and placental malaria. This work adds to our understanding of how PfEMP1 is trafficked to the RBC membrane by defining the protein-protein interaction networks that function at the Maurer's clefts controlling PfEMP1 loading and unloading. We characterize a protein needed for virulence protein trafficking and provide new insights into the mechanisms for host cell remodeling, parasite survival within the host, and virulence.

• Authors: Emma McHugh, Olivia M S Carmo, Adam Blanch, Oliver Looker, Boyin Liu, Snigdha Tiash, Dean Andrew, Steven Batinovic, Andy J Y Low, Hyun-Jung Cho, Paul McMillan, Leann Tilley, Matthew W A Dixon
• Journal: mBio (mBio) Vol. 11 Issue 2 (03 17 2020) ISSN: 2150-7511 [Electronic] United States
• PMID: 32184257 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 McHugh et al.

Chemical References

• Carrier Proteins
• Membrane Proteins
• Protozoan Proteins
• erythrocyte membrane protein 1, Plasmodium falciparum

Topics

• Carrier Proteins (metabolism)
• Cell Line
• Erythrocyte Membrane (metabolism, parasitology)
• Erythrocytes (cytology, parasitology)
• Host-Parasite Interactions
• Humans
• Membrane Proteins
• Plasmodium falciparum (genetics, metabolism, pathogenicity)
• Protein Interaction Maps
• Protein Transport
• Protozoan Proteins (genetics, metabolism)