Yaba monkey tumor virus encodes a functional inhibitor of interleukin-18.
Interleukin-18 (IL-18) is a critical proinflammatory cytokine whose extracellular bioactivity is regulated by a cellular IL-18 binding protein (IL-18BP). Many poxviruses have acquired variants of this IL-18BP gene, some of which have been shown to act as viral virulence factors. Yaba monkey tumor virus (YMTV) encodes a related family member, 14L, which is similar to the orthopoxvirus IL-18BPs. YMTV 14L was expressed from a baculovirus system and tested for its ability to bind and inhibit IL-18. We found that YMTV 14L bound both human IL-18 (hIL-18) and murine IL-18 with high affinity, at 4.1 nM and 6.5 nM, respectively. YMTV 14L was able to fully sequester hIL-18 but could only partially inhibit the biological activity of hIL-18 as measured by gamma interferon secretion from KG-1 cells. Additionally, 17 hIL-18 point mutants were tested by surface plasmon resonance for their ability to bind to YMTV 14L. Two clusters of hIL-18 surface residues were found to be important for the hIL-18-YMTV 14L interaction, in contrast to results for the Variola virus IL-18BP, which has been shown to primarily interact with a single cluster of three amino acids. The altered binding specificity of YMTV 14L most likely represents an adaptation resulting in increased fitness of the virus and affirms the plasticity of poxviral inhibitor domains that target cytokines like IL-18.
Nazarian
Steven H
SH
University of Florida, 1600 SW Archer Road, ARB Room R4-295, P.O. Box 100332, Gainesville, FL 32610, USA.
Rahman
Masmudur M
MM
Werden
Steven J
SJ
Villeneuve
Danielle
D
Meng
Xiangzhi
X
Brunetti
Craig
C
Valeriano
Chalice
C
Wong
Christina
C
Singh
Rajkumari
R
Barrett
John W
JW
Xiang
Yan
Y
McFadden
Grant
G
D002460:Cell Line; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000037:antagonists & inhibitors*; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020349:Surface Plasmon Resonance; D014764:Viral Proteins / Q000502:physiology*; D014999:Yaba monkey tumor virus / Q000276:immunology*
D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D014764:Viral Proteins; C118370:interleukin-18 binding protein; D007371:Interferon-gamma