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Nat Microbiol. 2018 Jan;3(1):17-25. doi: 10.1038/s41564-017-0054-x. Epub 2017 Nov 6.

Plasmodium UIS3 sequesters host LC3 to avoid elimination by autophagy in hepatocytes.

Author information

1
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
2
Department of Molecular Microbiology, Center for Infectious Disease Research, Washington University School of Medicine, St Louis, MO, USA.
3
Parasitology Department of Infectious Diseases, University of Heidelberg Medical School, Heidelberg, Germany.
4
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal. mmota@medicina.ulisboa.pt.

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.

PMID:
29109477
PMCID:
PMC5739284
DOI:
10.1038/s41564-017-0054-x
[Indexed for MEDLINE]
Free PMC Article

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