PMID- 35398099
OWN - NLM
STAT- MEDLINE
DCOM- 20220603
LR  - 20220716
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 298
IP  - 5
DP  - 2022 May
TI  - Structural basis of human IL-18 sequestration by the decoy receptor IL-18 binding 
      protein in inflammation and tumor immunity.
PG  - 101908
LID - S0021-9258(22)00348-9 [pii]
LID - 10.1016/j.jbc.2022.101908 [doi]
LID - 101908
AB  - 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.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Detry, Sam
AU  - Detry S
AD  - Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent 
      University, Ghent, Belgium; Unit for Structural Biology, VIB Center for 
      Inflammation Research, Ghent, Belgium.
FAU - Andries, Julie
AU  - Andries J
AD  - Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent 
      University, Ghent, Belgium; Unit for Structural Biology, VIB Center for 
      Inflammation Research, Ghent, Belgium.
FAU - Bloch, Yehudi
AU  - Bloch Y
AD  - Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent 
      University, Ghent, Belgium; Unit for Structural Biology, VIB Center for 
      Inflammation Research, Ghent, Belgium.
FAU - Gabay, Cem
AU  - Gabay C
AD  - Division of Rheumatology, Department of Medicine, Geneva University Hospitals & 
      Faculty of Medicine University of Geneva, Geneva 14, Switzerland.
FAU - Clancy, Danielle M
AU  - Clancy DM
AD  - Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent 
      University, Ghent, Belgium; Unit for Structural Biology, VIB Center for 
      Inflammation Research, Ghent, Belgium.
FAU - Savvides, Savvas N
AU  - Savvides SN
AD  - Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent 
      University, Ghent, Belgium; Unit for Structural Biology, VIB Center for 
      Inflammation Research, Ghent, Belgium. Electronic address: 
      savvas.savvides@ugent.be.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220406
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (IL18 protein, human)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Interleukin-18)
RN  - 0 (interleukin-18 binding protein)
SB  - IM
MH  - COVID-19/immunology
MH  - Humans
MH  - Inflammation
MH  - *Intercellular Signaling Peptides and Proteins
MH  - Interleukin-18/*metabolism
MH  - Neoplasms/immunology
PMC - PMC9111989
OTO - NOTNLM
OT  - autoimmunity
OT  - cancer therapy
OT  - crystal structure
OT  - cytokine
OT  - infectious disease
OT  - inflammation
OT  - interleukin
OT  - protein complex
OT  - protein structure
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2022/04/11 06:00
MHDA- 2022/06/07 06:00
PMCR- 2022/04/06
CRDT- 2022/04/10 20:23
PHST- 2022/02/14 00:00 [received]
PHST- 2022/04/03 00:00 [revised]
PHST- 2022/04/04 00:00 [accepted]
PHST- 2022/04/11 06:00 [pubmed]
PHST- 2022/06/07 06:00 [medline]
PHST- 2022/04/10 20:23 [entrez]
PHST- 2022/04/06 00:00 [pmc-release]
AID - S0021-9258(22)00348-9 [pii]
AID - 101908 [pii]
AID - 10.1016/j.jbc.2022.101908 [doi]
PST - ppublish
SO  - J Biol Chem. 2022 May;298(5):101908. doi: 10.1016/j.jbc.2022.101908. Epub 2022 
      Apr 6.