title: An interleukin-6 receptor-dependent molecular switch mediates signal transduction of the IL-27 cytokine subunit p28 (IL-30) via a gp130 protein receptor homodimer.
abstract: IL-27 consists of the cytokine subunit p28 and the non-signaling α-receptor EBI3. p28 was shown to additionally act via the non-signaling membrane-bound IL-6 α-receptor (IL-6R) as an agonistic cytokine but also as a gp130 β-receptor antagonist, leading to inhibition of IL-6 signaling. Here, we developed a strategy for bacterial expression, purification, and refolding of murine p28. We show that p28 did not interfere with IL-6- or IL-27-induced signaling, indicating that p28 has no antagonistic properties. Moreover, we demonstrate that murine p28 acts as an agonistic cytokine via the murine and human IL-6R, indicating that p28 exhibits no species specificity. p28 was able to induce p28-trans-signaling via the soluble IL-6R (sIL-6R), a characteristic property that was initially described for trans-signaling of IL-6 via the sIL-6R. Of notice, p28/sIL-6R trans-signaling was inhibited by the IL-6 trans-signaling antagonist, soluble gp130. At higher concentrations, p28 but not IL-6 was able to induce signaling even in the absence of IL-6R or EBI3. Although IL-27 signals via a heterodimer of the β-receptor chains gp130 and Wsx-1, p28/IL-6R specifically recruits two gp130 β-receptor chains for signal transduction. The binding of p28 to a gp130/Wsx-1 heterodimer or a gp130 homodimer is highly selective and controlled by a novel molecular switch induced by EBI3 or IL-6R, respectively.
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
authors.forename: Björn
authors.initials: B
authors.lastname: Spudy
authors.forename: Samadhi
authors.initials: S
authors.lastname: Aparicio-Siegmund
authors.forename: Georg H
authors.initials: GH
authors.lastname: Waetzig
authors.forename: Jan
authors.initials: J
authors.lastname: Sommer
authors.forename: Christoph
authors.initials: C
authors.lastname: Hölscher
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.forename: Inken
authors.initials: I
authors.lastname: Lorenzen
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D055503:Protein Multimerization / Q000502:physiology*; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C112441:IL27RA protein, human; C494199:IL6ST protein, human; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; C494200:Il6st protein, mouse; D007378:Interleukins; C464565:MYDGF protein, human; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050822:Cytokine Receptor gp130