IL-1 Family Cytokines Use Distinct Molecular Mechanisms to Signal through Their Shared Co-receptor

Abstract

Summary Within the interleukin 1 (IL-1) cytokine family, IL-1 receptor accessory protein (IL-1RAcP) is the co-receptor for eight receptor:cytokine pairs, including cytokines IL-1β and IL-33. Unlike for IL-1β, no structure of the IL-33 signaling complex exists that includes both its cognate receptor, ST2, and the shared co-receptor IL-1RAcP, which we now present here. Although the IL-1β and IL-33 complexes shared structural features and engaged identical molecular surfaces of IL-1RAcP, these cytokines had starkly different strategies for co-receptor engagement and signal activation. Our data suggested that IL-1β bound to IL-1RI to properly present the cytokine to IL-1RAcP, while IL-33 bound to ST2 in order to conformationally constrain the cognate receptor in an IL-1RAcP-receptive state. These findings indicated that IL-1 family cytokines use distinct molecular mechanisms to signal through their shared co-receptor, and provide the foundation from which to design new therapies to target IL-33 signaling.

Comparative Analyses of the Conformational Dynamics Between the Soluble and Membrane-Bound Cytokine Receptors

“…The ectodomain consists of three consecutive immunoglobulin-like C2 type-1,2,3 domains (denoted as D1-D3) connected by short linkers. The current model of the IL-1 pathway activation suggests that the IL-1 cytokine binds to its cognate IL-1R to recruit a second IL-1R member forming a hetero-trimeric protein complex and causing dimerization of TIR domains for downstream signaling 5 . Activation of the IL-1 pathway by extracellular cytokines can be regulated by negative or decoy receptors.…”

“…Among the IL-1R members, ST2 is expressed on hematopoietic cells including T helper type 2 (Th2) cells, group 2 innate lymphoid cells (ILC2), regulatory T cells (Tregs) and mast cells 9,10 . Membrane-bound ST2 binds with the only known ligand IL-33 to recruits IL-1RAcP resulting in TIR domain dimerization between ST2 and IL-1RAcP 5,11 . Signal transduction via the ST2/IL-33 pathway leads to p38 MAP kinases phosphorylation and nuclear factor (NF)-κB activation 11 .…”

“…Although antibodies therapeutics targeting the extracellular domains of cytokine receptors 22,24 can recognize specific epitopes, no selectivity between the two forms has been reported. We 25 and other groups 5,26 have studied the conformations of the ectodomain of ST2 (ST2 ECD ) using Small Angle X-ray scattering (SAXS) and computational simulations. These data showed that ST2 ECD possess high conformational flexibility.…”

From proteomics to discovery of first-in-class ST2 inhibitors active in vivo

“…On ST2 + CD4 + T cells, ligation of IL-33 with ST2 recruits IL-1R accessory protein (IL-1RAcP) and activates nuclear factor (NF)-κB and p38 MAP kinases via the ST2/IL-33 axis (27,28). A recent mechanistic study (29) further elucidated that binding of IL-33 with ST2 reduces ST2 mobility to engage additional interaction with IL-1RAcP in the IL-1RAcP-ST2-IL-33 complex. Activation of the Soluble cytokine receptors function as decoy receptors to attenuate cytokine-mediated signaling and modulate downstream cellular responses.…”

Interleukin-1 single nucleotide polymorphisms as risk factors for susceptibility of inflammatory bowel disease: an Iraqi Arab population-based study

“…The first two interleukins (IL-1α and IL-1β) are structurally related and recognize the same receptor (IL-1R), while IL-1RA binds IL-1R and blocks the activities of IL-1α and IL-1β [9]. IL-1 is mainly produced by activated monocytes and macrophages, and acts systemically and locally, while IL-1RA is produced by hepatocytes during the inflammatory acute-phase response, probably to control IL-1 effects [10]. An imbalance between IL-1 and IL-1RA production has been observed in mucosal biopsies obtained from inflamed colonic tissue of IBD patients, and an IL-1RA administration to rabbit model of dextraninduced colitis prevented mucosal inflammation and necrosis [11].…”