RRC ID 67312
Author Real E, Rodrigues L, Cabal GG, Enguita FJ, Mancio-Silva L, Mello-Vieira J, Beatty W, Vera IM, Zuzarte-Luís V, Figueira TN, Mair GR, Mota MM.
Title Plasmodium UIS3 sequesters host LC3 to avoid elimination by autophagy in hepatocytes.
Journal Nat Microbiol
Abstract The causative agent of malaria, Plasmodium, replicates inside a membrane-bound parasitophorous vacuole (PV), which shields this intracellular parasite from the cytosol of the host cell 1 . One common threat for intracellular pathogens is the homeostatic process of autophagy, through which cells capture unwanted intracellular material for lysosomal degradation 2 . During the liver stage of a malaria infection, Plasmodium parasites are targeted by the autophagy machinery of the host cell, and the PV membrane (PVM) becomes decorated with several autophagy markers, including LC3 (microtubule-associated protein 1 light chain 3) 3,4 . Here we show that Plasmodium berghei parasites infecting hepatic cells rely on the PVM transmembrane protein UIS3 to avoid elimination by host-cell-mediated autophagy. We found that UIS3 binds host LC3 through a non-canonical interaction with a specialized surface on LC3 where host proteins with essential functions during autophagy also bind. UIS3 acts as a bona fide autophagy inhibitor by competing with host LC3-interacting proteins for LC3 binding. Our work identifies UIS3, one of the most promising candidates for a genetically attenuated vaccine against malaria 5 , as a unique and potent mediator of autophagy evasion in Plasmodium. We propose that the protein-protein interaction between UIS3 and host LC3 represents a target for antimalarial drug development.
Volume 3(1)
Pages 17-25
Published 2018-1-1
DOI 10.1038/s41564-017-0054-x
PII 10.1038/s41564-017-0054-x
PMID 29109477
PMC PMC5739284
MeSH Animals Autophagosomes / metabolism Autophagy / physiology* Cell Line HEK293 Cells Hep G2 Cells Hepatocytes / parasitology Hepatocytes / pathology* Hepatocytes / ultrastructure Host-Pathogen Interactions Humans Malaria / parasitology* Malaria / pathology* Malaria / physiopathology Male Membrane Proteins / genetics Membrane Proteins / metabolism* Mice Mice, Inbred C57BL Microtubule-Associated Proteins / metabolism* Models, Molecular Plasmodium berghei / genetics* Plasmodium berghei / metabolism Plasmodium berghei / pathogenicity Protein Binding Protozoan Proteins / genetics Protozoan Proteins / metabolism Vacuoles / metabolism
IF 15.54
Human and Animal Cells Atg5^(+/+)MEF(RCB2710) Atg5^(-/-)MEF(RCB2711)