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Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF

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Abstract
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.
Keywords
COMPLEX, INTERLEUKIN-2, COWPOX VIRUS, SYSTEM, ORF VIRUS, VACCINIA VIRUS, INHIBITOR, COLONY-STIMULATING FACTOR, CHEMOKINE-BINDING-PROTEIN, CRYSTAL-STRUCTURE

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Chicago
Félix, Jan, Eaazhisai Kandiah, Steven De Munck, Yehudi Bloch, Gydo CP van Zundert, Kris Pauwels, Ann Dansercoer, et al. 2016. “Structural Basis of GM-CSF and IL-2 Sequestration by the Viral Decoy Receptor GIF.” Nature Communications 7.
APA
Félix, J., Kandiah, E., De Munck, S., Bloch, Y., van Zundert, G. C., Pauwels, K., Dansercoer, A., et al. (2016). Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF. NATURE COMMUNICATIONS, 7.
Vancouver
1.
Félix J, Kandiah E, De Munck S, Bloch Y, van Zundert GC, Pauwels K, et al. Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF. NATURE COMMUNICATIONS. 2016;7.
MLA
Félix, Jan et al. “Structural Basis of GM-CSF and IL-2 Sequestration by the Viral Decoy Receptor GIF.” NATURE COMMUNICATIONS 7 (2016): n. pag. Print.
@article{8173451,
  abstract     = {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.},
  articleno    = {13228},
  author       = {Félix, Jan and Kandiah, Eaazhisai and De Munck, Steven and Bloch, Yehudi and van Zundert, Gydo CP and Pauwels, Kris and Dansercoer, Ann and Novanska, Katka and Read, Randy J and Bonvin, Alexandre MJJ and Vergauwen, Bjorn and Verstraete, Kenneth and Gutsche, Irina and Savvides, Savvas},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  keywords     = {COMPLEX,INTERLEUKIN-2,COWPOX VIRUS,SYSTEM,ORF VIRUS,VACCINIA VIRUS,INHIBITOR,COLONY-STIMULATING FACTOR,CHEMOKINE-BINDING-PROTEIN,CRYSTAL-STRUCTURE},
  language     = {eng},
  pages        = {13},
  title        = {Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF},
  url          = {http://dx.doi.org/10.1038/ncomms13228},
  volume       = {7},
  year         = {2016},
}

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