Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF.
Subversion of the host immune system by viruses is often mediated by molecular decoys that sequester host proteins pivotal to mounting effective immune responses. The widespread mammalian pathogen parapox Orf virus deploys GIF, a member of the poxvirus immune evasion superfamily, to antagonize GM-CSF (granulocyte macrophage colony-stimulating factor) and IL-2 (interleukin-2), two pleiotropic cytokines of the mammalian immune system. However, structural and mechanistic insights into the unprecedented functional duality of GIF have remained elusive. Here we reveal that GIF employs a dimeric binding platform that sequesters two copies of its target cytokines with high affinity and slow dissociation kinetics to yield distinct complexes featuring mutually exclusive interaction footprints. We illustrate how GIF serves as a competitive decoy receptor by leveraging binding hotspots underlying the cognate receptor interactions of GM-CSF and IL-2, without sharing any structural similarity with the cytokine receptors. Our findings contribute to the tracing of novel molecular mimicry mechanisms employed by pathogenic viruses.
Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.|VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium.
Jan
J
Felix
University Grenoble Alpes, CNRS, CEA, IBS, F-38044 Grenoble, France.
Eaazhisai
E
Kandiah
Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.|VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium.
Steven
S
De Munck
Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.|VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium.
Yehudi
Y
Bloch
Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, 3584CH Utrecht, The Netherlands.
Gydo C P
GC
van Zundert
VIB Structural Biology Research Center, Vrije Universiteit Brussel, Pleinlaan 2, 1040 Brussels, Belgium.
Kris
K
Pauwels
Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.|VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium.
Ann
A
Dansercoer
Masaryk University &CEITEC, 62500 Brno, Czech Republic.
Katka
K
Novanska
Department of Haematology, University of Cambridge School of Clinical Medicine, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge Biomedical Campus Box 139, Cambridge CB2 0XY, UK.
Randy J
0000-0001-8273-0047
RJ
Read
Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, 3584CH Utrecht, The Netherlands.
Alexandre M J J
AM
Bonvin
Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.
Bjorn
B
Vergauwen
Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.|VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium.
Kenneth
K
Verstraete
University Grenoble Alpes, CNRS, CEA, IBS, F-38044 Grenoble, France.
Irina
I
Gutsche
Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.|VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium.
Savvas N
SN
Savvides
D018360:Crystallography, X-Ray; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D018157:Parapoxvirus / Q000276:immunology* / Q000378:metabolism; D011213:Poxviridae Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D011485:Protein Binding; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
C403419:GIF protein, orf virus; D007376:Interleukin-2; D046912:Multiprotein Complexes; D014764:Viral Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor