@article{8761326,
  abstract     = {{Human Interleukin-18 (IL-18) is an omnipresent proinflammatory cytokine of the IL-1 family with central roles in autoimmune and inflammatory diseases and serves as a staple biomarker in the evaluation of inflammation in physiology and disease, including the inflammatory phase of COVID-19. The sequestration of IL-18 by its soluble decoy receptor IL-18-Binding Protein (IL-18BP) is critical to the regulation of IL-18 activity. Since an imbalance in expression and circulating levels of IL-18 is associated with disease, structural insights into how IL-18BP outcompetes binding of IL-18 by its cognate cell-surface receptors are highly desirable; however, the structure of human IL-18BP in complex with IL-18 has been elusive. Here, we elucidate the sequestration mechanism of human IL-18 mediated by IL-18BP based on the crystal structure of the IL-18:IL-18BP complex. These detailed structural snapshots reveal the interaction landscape leading to the ultra-high affinity of IL-18BP toward IL-18 and identify substantial differences with respect to previously characterized complexes of IL-18 with IL-18BP of viral origin. Furthermore, our structure captured a fortuitous higher-order assembly between IL-18 and IL-18BP coordinated by a disulfide-bond distal to the binding surface connecting IL-18 and IL-18BP molecules from different complexes, resulting in a novel tetramer with 2:2 stoichiometry. This tetrapartite assembly was found to restrain IL-18 activity more effectively than the canonical 1:1 complex. Collectively, our findings provide a framework for innovative, structure-driven therapeutic strategies and further functional interrogation of IL-18 in physiology and disease.}},
  articleno    = {{101908}},
  author       = {{Detry, Sammy and Andries, Julie and Bloch, Yehudi and Gabay, Cem and Clancy, Danielle and Savvides, Savvas}},
  issn         = {{0021-9258}},
  journal      = {{JOURNAL OF BIOLOGICAL CHEMISTRY}},
  keywords     = {{Cell Biology,Molecular Biology,Biochemistry,GAMMA-INDUCING FACTOR,HIGH-LEVEL EXPRESSION,IFN-GAMMA,HUMAN INTERLEUKIN-18,RHEUMATOID-ARTHRITIS,BIOLOGICAL-ACTIVITY,MATURE FORM,INTERFERON,ACTIVATION,CYTOKINE}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{16}},
  title        = {{Structural basis of human IL-18 sequestration by the decoy receptor IL-18 binding protein in inflammation and tumor immunity}},
  url          = {{http://doi.org/10.1016/j.jbc.2022.101908}},
  volume       = {{298}},
  year         = {{2022}},
}

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