Abstract
Interleukin 18 (IL18) is a cytokine that plays an important role in inflammation as well as host defense against microbes. Mammals encode a soluble inhibitor of IL18 termed IL18 binding protein (IL18BP) that modulates IL18 activity through a negative feedback mechanism. Many poxviruses encode homologous IL18BPs, which contribute to virulence. Previous structural and functional studies on IL18 and IL18BPs revealed an essential binding hot spot involving a lysine on IL18 and two aromatic residues on IL18BPs. The aromatic residues are conserved among the very diverse mammalian and poxviruses IL18BPs with the notable exception of yatapoxvirus IL18BPs, which lack a critical phenylalanine residue. To understand the mechanism by which yatapoxvirus IL18BPs neutralize IL18, we solved the crystal structure of the Yaba-Like Disease Virus (YLDV) IL18BP and IL18 complex at 1.75 Å resolution. YLDV-IL18BP forms a disulfide bonded homo-dimer engaging IL18 in a 2∶2 stoichiometry, in contrast to the 1∶1 complex of ectromelia virus (ECTV) IL18BP and IL18. Disruption of the dimer interface resulted in a functional monomer, however with a 3-fold decrease in binding affinity. The overall architecture of the YLDV-IL18BP:IL18 complex is similar to that observed in the ECTV-IL18BP:IL18 complex, despite lacking the critical lysine-phenylalanine interaction. Through structural and mutagenesis studies, contact residues that are unique to the YLDV-IL18BP:IL18 binding interface were identified, including Q67, P116 of YLDV-IL18BP and Y1, S105 and D110 of IL18. Overall, our studies show that YLDV-IL18BP is unique among the diverse family of mammalian and poxvirus IL-18BPs in that it uses a bivalent binding mode and a unique set of interacting residues for binding IL18. However, despite this extensive divergence, YLDV-IL18BP binds to the same surface of IL18 used by other IL18BPs, suggesting that all IL18BPs use a conserved inhibitory mechanism by blocking a putative receptor-binding site on IL18.
Highlights
Poxviruses are a family of large, complex DNA viruses, infecting a variety of organisms including insects, reptiles, birds and mammals [1]
Previous structural and functional studies revealed residues at Interleukin 18 (IL18):IL18 binding protein (IL18BP) interface that are critical for the high-affinity binding, including a phenylalanine on IL18BPs, which is conserved among most IL18BPs with the notable exception of yatapoxvirus IL18BPs
Through mutagenesis and functional studies, we found a set of interacting residues that are unique for the association of Yaba-Like Disease Virus (YLDV)-IL18BP and IL18, likely compensating for the lack of the interactions involving the conserved phenylalanine
Summary
Poxviruses are a family of large, complex DNA viruses, infecting a variety of organisms including insects, reptiles, birds and mammals [1]. As an immune evasion strategy, poxviruses encode an assortment of decoy receptors for chemokines and cytokines [3]. One such strategy for evasion of the host immune response is through modulation of the interleukin 18 (IL18) signaling pathway. IL18 is a pro-inflammatory cytokine belonging to the interleukin 1 superfamily and plays an important role in both innate and acquired immune responses by inducing interferon-c (IFN-c) production from T lymphocytes and macrophages while enhancing the cytotoxicity of natural killer cells [4]. Homologues of IL18BPs are encoded by many poxviruses including molluscum contagiosum virus and orthopoxviruses [6,7] such as variola virus, the causative agent of smallpox
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