Non-Canonical Interleukin 23 Receptor Complex Assembly

Schröder, Jutta; Moll, Jens M.; Baran, Paul; Grötzinger, Joachim; Scheller, Jürgen; Floß, Doreen M.

doi:10.1074/jbc.m114.617597

Cited by 37 publications

(30 citation statements)

References 39 publications

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“…So far, no signaling role of IL-12Rβ1 in the receptor complex apart from activation of a Janus kinase has been assigned 20 . Consistently, using our synthetic receptors, we induced IL-23R homodimeric receptor complexes, as we have recently suggested 30 , 31 . Although the general activation of signaling pathways appeared to be similar to IL-23 signaling, gene-array analysis revealed a reduced number of regulated genes when compared to heterodimeric signaling.…”

Section: Discussionsupporting

confidence: 90%

Synthetic cytokine receptors transmit biological signals using artificial ligands

et al. 2018

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Cytokine-induced signal transduction is executed by natural biological switches, which among many others control immune-related processes. Here, we show that synthetic cytokine receptors (SyCyRs) can induce cytokine signaling using non-physiological ligands. High-affinity GFP- and mCherry-nanobodies were fused to transmembrane and intracellular domains of the IL-6/IL-11 and IL-23 cytokine receptors gp130 and IL-12Rβ1/IL-23R, respectively. Homo- and heterodimeric GFP:mCherry fusion proteins as synthetic cytokine-like ligands were able to induce canonical signaling in vitro and in vivo. Using SyCyR ligands, we show that IL-23 receptor homodimerization results in its activation and IL-23-like signal transduction. Moreover, trimeric receptor assembly induces trans-phosphorylation among cytokine receptors with associated Janus kinases. The SyCyR technology allows biochemical analyses of transmembrane receptor signaling in vitro and in vivo, cell-specific activation through SyCyR ligands using transgenic animals and possible therapeutic regimes involving non-physiological targets during immunotherapy.

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Section: Discussionsupporting

confidence: 90%

Synthetic cytokine receptors transmit biological signals using artificial ligands

et al. 2018

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“…5J), indicating that the deletion did not disturb the structure of mIL-23R. As already shown, HIL-23 binds to the independently expressed extracellular domains of either IL-12R␤1 or IL-23R; accordingly, IL-12R␤1 was dispensable for this experiment (7).…”

Section: Resultsmentioning

confidence: 75%

“…IL-23R is composed of an N-terminal immunoglobulin-like domain 1 (D1) and a cytokine binding module (CBM) formed by domains 2 and 3 (D2 and D3), which carry binding sites for IL-23 (7). The cytokine binding domains are connected to the transmembrane region by a stalk region of 37 amino acids (aa) in humans and 36 amino acids in mice, followed by the transmembrane domain and the intracellular region.…”

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confidence: 99%

Synthetic Deletion of the Interleukin 23 Receptor (IL-23R) Stalk Region Led to Autonomous IL-23R Homodimerization and Activation

Hummel

Ackfeld

Schönberg

et al. 2017

Molecular and Cellular Biology

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Interleukin 23 (IL-23) regulates the development of TH17 cells, which are important for antimicrobial and antifungal responses and autoimmune and chronic inflammatory diseases. IL-23-induced Jak/STAT signaling is mediated via the heterodimeric IL-23 receptor (IL-23R)-IL-12 receptor ␤1 (IL-12R␤1) complex. The typical signal-transducing receptor of the IL-6/IL-12 family contains three extracellularmembrane-proximal fibronectin type III (FNIII) domains, which are not involved in cytokine binding but are mandatory for signal transduction. In place of FNIII-type domains, IL-23R has a structurally undefined stalk. We hypothesized that the IL-23R stalk acts as a spacer to position the cytokine binding domains at a defined distance from the plasma membrane to enable signal transduction. Minor deletions of the murine, but not of the human, IL-23R stalk resulted in unresponsiveness to IL-23. Complete deletion of the human IL-23R stalk and the extended murine IL-23R stalk, including a 20-amino-acid-long duplication of domain 3, however, induced ligandindependent, autonomous receptor activation, as determined by STAT3 phosphorylation and cell proliferation. Ligand-independent, autonomous activity was caused by IL-23R homodimers and was independent of IL-12R␤1. Our data show that deletion of the stalk results in biologically active IL-23R homodimers, thereby creating an asyet-undescribed receptor complex of the IL-6/IL-12 cytokine family.KEYWORDS IL-23 receptor, IL-23 signaling T he proinflammatory cytokine interleukin 23 (IL-23) is a member of the IL-6/IL-12 family (1). IL-23 regulates the development of TH17 cells, which are important mediators of antimicrobial and antifungal responses. Furthermore, they are involved in the pathogenesis of autoimmune and chronic inflammatory diseases (2). IL-23 binding initiates the heterodimerization of the ␤ receptor chains IL-23 receptor (IL-23R) and IL-12R␤1. Subsequently, receptor-associated tyrosine kinase 2 (Tyk2) and Janus kinase 2 (Jak2) activate independent signaling pathways, including the Jak/STAT, the mitogenactivated protein kinase (MAPK)/Erk, and the phosphatidylinositol 3-kinase (PI3K)/Akt pathways. IL-23 predominantly activates STAT3 and to a lesser extent STAT1, STAT4, and STAT5 (3, 4).IL-12R␤1 was considered a ligand binding receptor (5). However, it was demonstrated that IL-12R␤1 is important for kinase binding and activation. Moreover, association of Jak2 with IL-23R is mandatory for IL-23 signaling, whereas Tyk2 seems to be dispensable (6).IL-23R is composed of an N-terminal immunoglobulin-like domain 1 (D1) and a cytokine binding module (CBM) formed by domains 2 and 3 (D2 and D3), which carry

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“…Oppmann and colleagues termed this novel composite cytokine IL-23. Whereas human IL-23p19 is not secreted, a small amount of murine IL-23p19 was detected in cell culture supernatants of HEK293T and COS-7 cells [ 9 , 68 ]. IL-23p19 and IL-12p35 subunits overlap, and their four-helix bundles match one another despite their low sequence homology of 15% ( Figure 2 D) [ 69 ].…”

Section: Structural Features Of Il-12 Il-23 and Their Receptorsmentioning

confidence: 99%

IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions

Floß

Moll

Scheller

2020

Cells

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Cytokines of the IL-12 family show structural similarities but have distinct functions in the immune system. Prominent members of this cytokine family are the pro-inflammatory cytokines IL-12 and IL-23. These two cytokines share cytokine subunits and receptor chains but have different functions in autoimmune diseases, cancer and infections. Accordingly, structural knowledge about receptor complex formation is essential for the development of new therapeutic strategies preventing and/or inhibiting cytokine:receptor interaction. In addition, intracellular signaling cascades can be targeted to inhibit cytokine-mediated effects. Single nucleotide polymorphisms can lead to alteration in the amino acid sequence and thereby influencing protein functions or protein–protein interactions. To understand the biology of IL-12 and IL-23 and to establish efficient targeting strategies structural knowledge about cytokines and respective receptors is crucial. A highly efficient therapy might be a combination of different drugs targeting extracellular cytokine:receptor assembly and intracellular signaling pathways.

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Non-Canonical Interleukin 23 Receptor Complex Assembly

Cited by 37 publications

References 39 publications

Synthetic cytokine receptors transmit biological signals using artificial ligands

Synthetic cytokine receptors transmit biological signals using artificial ligands

Synthetic Deletion of the Interleukin 23 Receptor (IL-23R) Stalk Region Led to Autonomous IL-23R Homodimerization and Activation

IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions

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