Journal Article

Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Dustin, Michael L., Higgins, Matthew K., Harrison, Thomas E., Reid, Adam J., Mørch, Alexander M., Arase, Hisashi, Sakoguchi, Akihito, Felce, James H.

2020

Overview

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 erythrocytes 1 . Some RIFINs can bind to inhibitory immune receptors, and these RIFINs act as targets for unusual antibodies that contain a LAIR1 ectodomain 2 – 4 or as ligands for LILRB1 5 . RIFINs stimulate the activation of and signalling by LILRB1 5 , 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. The structure of a RIFIN–LILRB1 complex reveals that a subset of RIFINs of Plasmodium falciparum mimics the binding mode of the natural ligand of human LILRB1 and suppress the function of natural killer cells in humans.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 631/250/255 / 631/326/417 / 82/103 / 82/80 / 82/83 / Amino Acid Sequence / Analysis / Animals / Antibodies / Antibody-Dependent Cell Cytotoxicity - immunology / Antibody-dependent cell-mediated cytotoxicity / Binding / Binding sites / Binding Sites - immunology / Cell activation / Cytotoxicity / Erythrocytes / Genetic aspects / Histocompatibility Antigens Class I - immunology / Humanities and Social Sciences / Humans / Hydrogen bonds / Immune response / Immunoglobulins / Immunological synapses / Immunology / Killer Cells, Natural - cytology / Killer Cells, Natural - immunology / Leukocyte Immunoglobulin-like Receptor B1 - chemistry / Leukocyte Immunoglobulin-like Receptor B1 - immunology / Leukocyte Immunoglobulin-like Receptor B1 - metabolism / Ligands / Lipid Bilayers / Lipids / Lymphocyte Activation / Major histocompatibility complex / Malaria / Malaria, Falciparum - immunology / Malaria, Falciparum - parasitology / Membrane proteins / Membrane Proteins - chemistry / Membrane Proteins - genetics / Membrane Proteins - immunology / Membrane Proteins - metabolism / Models, Molecular / Molecular Mimicry - immunology / multidisciplinary / Mutation / Natural killer cells / Parasites / Perforin / Perforin - metabolism / Physiological aspects / Plasmodium falciparum / Proteins / Protozoan Proteins - chemistry / Protozoan Proteins - genetics / Protozoan Proteins - immunology / Protozoan Proteins - metabolism / Receptors / Science / Science (multidisciplinary) / Signal Transduction / Signaling / Signs and symptoms / Structure / Synapses / Toxicity / Transcriptional coactivators / Vector-borne diseases