Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Thomas E. Harrison, Alexander M. Mørch, James H. Felce, Akihito Sakoguchi, Adam J. Reid, Hisashi Arase, Michael L. Dustin and Matthew K. Higgins ()
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Thomas E. Harrison: University of Oxford
Alexander M. Mørch: University of Oxford
James H. Felce: University of Oxford
Akihito Sakoguchi: Osaka University
Adam J. Reid: Wellcome Sanger Institute
Hisashi Arase: Osaka University
Michael L. Dustin: University of Oxford
Matthew K. Higgins: University of Oxford

Nature, 2020, vol. 587, issue 7833, 309-312

Abstract: Abstract The Plasmodium species that cause malaria are obligate intracellular parasites, and disease symptoms occur when these parasites replicate in human blood. Despite the risk of immune detection, the parasite delivers proteins that bind to host receptors on the cell surfaces of infected erythrocytes. In the causative parasite of the most deadly form of malaria in humans, Plasmodium falciparum, RIFINs form the largest family of surface proteins displayed by erythrocytes1. Some RIFINs can bind to inhibitory immune receptors, and these RIFINs act as targets for unusual antibodies that contain a LAIR1 ectodomain2–4 or as ligands for LILRB15. RIFINs stimulate the activation of and signalling by LILRB15, which could potentially lead to the dampening of human immune responses. Here, to understand how RIFINs activate LILRB1-mediated signalling, we determine the structure of a RIFIN bound to LILRB1. We show that this RIFIN mimics the natural activating ligand of LILRB1, MHC class I, in its LILRB1-binding mode. A single mutation in the RIFIN disrupts the complex, blocks LILRB1 binding of all tested RIFINs and abolishes signalling in a reporter assay. In a supported lipid bilayer system, which mimics the activation of natural killer (NK) cells by antibody-dependent cell-mediated cytotoxicity, both RIFIN and MHC are recruited to the immunological synapse of NK cells and reduce the activation of NK cells, as measured by the mobilization of perforin. Therefore, LILRB1-binding RIFINs mimic the binding mode of the natural ligand of LILRB1 and suppress the function of NK cells.

Date: 2020
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DOI: 10.1038/s41586-020-2530-3

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