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

Eliana Real, Lénia Rodrigues, Ghislain G. Cabal, Francisco J. Enguita, Liliana Mancio-Silva, João Mello-Vieira, Wandy Beatty, Iset M. Vera, Vanessa Zuzarte-Luís, Tiago N. Figueira, Gunnar R. Mair, Maria M. Mota

Research output: Contribution to journalArticle

22 Scopus citations

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 cell1. One common threat for intracellular pathogens is the homeostatic process of autophagy, through which cells capture unwanted intracellular material for lysosomal degradation2. 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.

Original languageEnglish
Pages (from-to)17-25
Number of pages9
JournalNature microbiology
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2017

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    Real, E., Rodrigues, L., Cabal, G. G., Enguita, F. J., Mancio-Silva, L., Mello-Vieira, J., Beatty, W., Vera, I. M., Zuzarte-Luís, V., Figueira, T. N., Mair, G. R., & Mota, M. M. (2017). Plasmodium UIS3 sequesters host LC3 to avoid elimination by autophagy in hepatocytes. Nature microbiology, 3(1), 17-25. https://doi.org/10.1038/s41564-017-0054-x