Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein

Krumm, Brian E.; Meng, Xiangzhi; Li, Yongchao; Xiang, Yan; Deng, Junpeng

doi:10.1073/pnas.0809086106

Cited by 70 publications

(106 citation statements)

References 29 publications

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“…6c), explaining how 125-2H and IL-18BP are able to bind simultaneously. Our modeling, which was completed 2 years ago, is completely in accord with the recent IL-18⅐poxvirus IL-18BP crystal structure (55).…”

Section: -2h Is Specific For Human Il-18-the Human Il-18⅐125-2hsupporting

confidence: 61%

Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18

Argiriadi¹,

Xiang²,

et al. 2009

Journal of Biological Chemistry

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The unique cytokine interleukin-18 (IL-18) acts synergistically with IL-12 to regulate T-helper 1 and 2 lymphocytes and, as such, seems to underlie the pathogenesis of various autoimmune and allergic diseases. Several anti-IL-18 agents are in clinical development, including the recombinant human antibody ABT-325, which is entering trials for autoimmune diseases. Given competing cytokine/receptor and cytokine/receptor decoy interactions, understanding the structural basis for recognition is critical for effective development of anti-cytokine therapies. Here we report three crystal structures: the murine antibody 125-2H Fab fragment bound to human IL-18, at 1.5 Å resolution; the 125-2H Fab (2.3 Å ); and the ABT-325 Fab (1.5 Å ). These structures, along with human/mouse IL-18 chimera binding data, allow us to make three key observations relevant to the biology and antigenic recognition of IL-18 and related cytokines. First, several IL-18 residues shift dramatically (>10 Å ) upon binding 125-2H, compared with unbound IL-18 (Kato, Z., Jee, J., Shikano, H., Mishima, M., Ohki, I., Ohnishi, H., Li, A., Hashimoto, K., Matsukuma, E., Omoya, K., Yamamoto, Y., Yoneda, T., Hara, T., Kondo, N., and Shirakawa, M. (2003) Nat. Struct. Biol. 10, 966 -971). IL-18 thus exhibits plasticity that may be common to its interactions with other receptors. Related cytokines may exhibit similar plasticity. Second, ABT-325 and 125-2H differ significantly in combining site character and architecture, thus explaining their ability to bind IL-18 simultaneously at distinct epitopes. These data allow us to define the likely ABT-325 epitope and thereby explain the distinct neutralizing mechanisms of both antibodies. Third, given the high 125-2H potency, 10 well ordered water molecules are trapped upon complex formation in a cavity between two IL-18 loops and all six 125-2H complementarity-determining regions. Thus, counterintuitively, tight and specific antibody binding may in some cases be water-mediated. Interleukin (IL)3 -18 is a proinflammatory cytokine that participates in the regulation of innate and acquired immunity (2, 3). IL-18 acts alone or in concert with IL-12 to amplify the induction of proinflammatory and cytotoxic mediators, such as interferon-␥. For example, in IL-18 knock-out mice, levels of interferon-␥ and cytotoxic T cells decrease despite the presence of IL-12. Inhibition of IL-18 activity has been found to be beneficial in several autoimmune disease animal models (e.g. collagen-induced arthritis (4) and colitis (5)). Furthermore, IL-18 expression is dramatically increased by the chronic inflammatory state extant in human autoimmune diseases, such as rheumatoid arthritis (6), multiple sclerosis (7, 8), and Crohn's disease (9). These observations suggest that blockade of IL-18 may be a useful human therapeutic modality (10).Despite functional divergence from the IL-1 cytokine family, IL-18 shares many similarities with IL-1. First, human IL-18 is synthesized as a biologically inactive 24-kDa precursor. Like IL-1␤, IL-18 is act...

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Section: -2h Is Specific For Human Il-18-the Human Il-18⅐125-2hsupporting

confidence: 61%

Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18

Argiriadi¹,

Xiang²,

et al. 2009

Journal of Biological Chemistry

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“…Recently, the crystal structure of ECTV IL-18BP complexed with human IL-18 was solved. Upon binding, ECTV IL-18BP blocks a putative binding site on IL-18, and this prevents IFN-␥ induction by IL-18 (91). These studies are important for the rational design of inhibitors against the viral IL-18BP, which is a potential therapeutic target for the treatment of orthopoxvirus infections in general.…”

Section: Structural Proteomicsmentioning

confidence: 99%

Poxvirus Proteomics and Virus-Host Protein Interactions

Vliet

Mohamed

Zhang

et al. 2009

Microbiol Mol Biol Rev

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SUMMARY Studies of the functional proteins encoded by the poxvirus genome provide information about the composition of the virus as well as individual virus-virus protein and virus-host protein interactions, which provides insight into viral pathogenesis and drug discovery. Widely used proteomic techniques to identify and characterize specific protein-protein interactions include yeast two-hybrid studies and coimmunoprecipitations. Recently, various mass spectrometry techniques have been employed to identify viral protein components of larger complexes. These methods, combined with structural studies, can provide new information about the putative functions of viral proteins as well as insights into virus-host interaction dynamics. For viral proteins of unknown function, identification of either viral or host binding partners provides clues about their putative function. In this review, we discuss poxvirus proteomics, including the use of proteomic methodologies to identify viral components and virus-host protein interactions. High-throughput global protein expression studies using protein chip technology as well as new methods for validating putative protein-protein interactions are also discussed.

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“…Given the critical nature of the IL-18 -IL-18BP axis for regulating inflammatory responses of the skin, it is likely to be a critical factor governing the persistence of skin-tropic viruses. Indeed, poxviruses are known to encode functional IL-18BP homologues, which contribute to virus virulence by downregulating IL-18-mediated inflammatory responses (20). Despite the body of evidence regarding the importance of IL-18BP for regulating the epithelial inflammatory response, there is cur-rently no published observation of direct virus modulation of endogenous IL-18BP.…”

mentioning

confidence: 91%

Human Papillomavirus E7 Oncoprotein Increases Production of the Anti-Inflammatory Interleukin-18 Binding Protein in Keratinocytes

Richards

Doble

Wasson

et al. 2014

J Virol

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Human papillomavirus (HPV) can successfully evade the host immune response to establish a persistent infection. We show here that expression of the E7 oncoprotein in primary human keratinocytes results in increased production of interleukin-18 (IL-18) binding protein (IL-18BP). This anti-inflammatory cytokine binding protein is a natural antagonist of IL-18 and is necessary for skin homeostasis. We map increased IL-18BP production to the CR3 region of E7 and demonstrate that this ability is shared among E7 proteins from different HPV types. Furthermore, mutagenesis shows that increased IL-18BP production is mediated by a gamma-activated sequence (GAS) in the IL-18BP promoter. Importantly, the increased IL-18BP levels seen in E7-expressing keratinocytes are capable of diminishing IL-18-mediated CD4 lymphocyte activation. This study provides the first evidence for a virus protein that targets IL-18BP and further validates E7 as a key component of the HPV immune evasion armor. IMPORTANCEInfection with human papillomavirus is a leading cause of morbidity and mortality worldwide. This study demonstrates that the E7 protein increases production of the anti-inflammatory IL-18BP, a major regulator of epithelial homeostasis. A number of E7 proteins can increase IL-18BP production, and a region within the CR3 of E7 is necessary for mediating the increase. A consequence of increased IL-18BP production is a reduction in CD4-positive lymphocyte activation in response to IL-18 costimulation. These findings may shed light on the immune evasion abilities of HPV.

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Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein

Cited by 70 publications

References 29 publications

Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18

Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18

Poxvirus Proteomics and Virus-Host Protein Interactions

Human Papillomavirus E7 Oncoprotein Increases Production of the Anti-Inflammatory Interleukin-18 Binding Protein in Keratinocytes

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