Non-Canonical Interleukin 23 Receptor Complex Assembly

By Jutta Schröder, Jens M. Moll, Paul Baran, J. Grötzinger, J. Scheller, D. Floss. 2014

41 citations recorded by the source corpus.

Background: The heterodimeric cytokine IL-23 binds to a receptor complex consisting of IL-23R and IL-12Rβ1. Results: Binding of IL-23 to IL-12Rβ1 is mediated by domains 1 and 2 of p40. Conclusion: The IL-23·IL-23R·IL-12Rβ1 complex formation does not follow the classical “site I-II-III” architectural paradigm. Significance: The p40 subunit is shared by IL-23 and IL-12 and interacts directly with IL-12Rβ1. IL-23, composed of the cytokine subunit p19 and the soluble α receptor subunit p40, binds to a receptor complex consisting of the IL-23 receptor (IL-23R) and the IL-12 receptor β1 (IL-12Rβ1). Complex formation was hypothesized to follow the “site I-II-III” architectural paradigm, with site I of p19 being required for binding to p40, whereas sites II and III of p19 mediate binding to IL-12Rβ1 and IL-23R, respectively. Here we show that the binding mode of p19 to p40 and of p19 to IL-23R follow the canonical site I and III paradigm but that interaction of IL-23 to IL-12Rβ1 is independent of site II in p19. Instead, binding of IL-23 to the cytokine binding module of IL-12Rβ1 is mediated by domains 1 and 2 of p40 via corresponding site II amino acids of IL-12Rβ1. Moreover, domains 2 and 3 of p40 were sufficient for complex formation with p19 and to induce binding of p19 to IL-23R. The Fc-tagged fusion protein of p40_D2D3/p19 did, however, not act as a competitive IL-23 antagonist but, at higher concentrations, induced proliferation via IL-23R but independent of IL-12Rβ1. On the basis of our experimental validation, we propose a non-canonical topology of the IL-23·IL-23R·IL-12Rβ1 complex. Furthermore, our data help to explain why p40 is an antagonist of IL-23 and IL-12 signaling and show that site II of p19 is dispensable for IL-23 signaling.

Subfields: Dermatology, Immunology, Oncology

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Citations in the corpus

Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1 (2017, background): “This is because the functional role of this particular position had been postulated based on structural considerations of the receptor-free cytokine (Lupardus and Garcia, 2008), and has only recently been probed via reporter cellular assays in vitro (Schroder et al., 2015).”