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 malaria5, 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.

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The authors thank M. Komatsu (Tokyo Metropolitan Institute of Medical Science) for providing Atg3 MEFs, T. Finkel (NIH National Heart, Lung, and Blood Institute) for the Atg7 MEFs, F. Randow (MRC Laboratory of Molecular Biology) for the gift of p62-luciferase and GST-LC3 expression plasmids, Jacobus Pharmaceuticals for the WR99210 compound, A. Parreira for producing P. berghei-infected Anopheles mosquitoes, and S. Marques and K. Slavic for their help with parasite cloning. This work was supported by grants from the European Research Council (ERC‐2012‐StG_311502 to M.M.M.), Fundação para a Ciência e Tecnologia (EXCL/IMI-MIC/0056/2012 to M.M.M. and PTDC/IMI-MICC/1568/2012 to G.G.C.) and Institut Mérieux (MRG_20052016 to M.M.M). E.R. was the recipient of EMBO (ALTF 949-2008) and FCT (SFRH/BPD/68709/2010) fellowships. L.R. is the recipient of FCT fellowship SFRH/BPD/111323/2015. G.G.C. was sponsored by Marie Curie (PIEF-GA-2009-235864) and FCT (SFRH/BPD/74151/2010) fellowships. L.M.S. was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 242095 (EVIMalaR). V.Z.L. was sponsored by EMBO (ALTF 357-2009) and FCT (BPD-81953-2011) fellowships. I.M.V. and J.M.-V. were supported by NIH (1F32A11042-5 021) and FCT (SFRH/BD/52226/2013) fellowships, respectively.

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Author notes

  1. Eliana Real and Lénia Rodrigues contributed equally to this work.


  1. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

    • Eliana Real
    • , Lénia Rodrigues
    • , Ghislain G. Cabal
    • , Francisco J. Enguita
    • , Liliana Mancio-Silva
    • , João Mello-Vieira
    • , Iset M. Vera
    • , Vanessa Zuzarte-Luís
    • , Tiago N. Figueira
    •  & Maria M. Mota
  2. Department of Molecular Microbiology, Center for Infectious Disease Research, Washington University School of Medicine, St Louis, MO, USA

    • Wandy Beatty
  3. Parasitology Department of Infectious Diseases, University of Heidelberg Medical School, Heidelberg, Germany

    • Gunnar R. Mair


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E.R. and M.M.M. conceived and led the study and wrote the manuscript. E.R, L.R., G.G.C. and J.M.-V. performed the experiments, acquired the data, performed data analysis and interpreted results. F.J.E. performed molecular docking, protein purification and SPR analysis. Animal experimentation was conducted by L.M.-S., L.R., I.M.V. and V.Z.-L. W.B. performed electron microscopy analysis. Circular dichroism was performed by T.N.F. G.R.M. constructed plasmids for parasite transfections. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Maria M. Mota.

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