Dokument: Synthetic trimeric interleukin-6 receptor complexes with a STAT3 phosphorylation dominated activation profile
| Titel: | Synthetic trimeric interleukin-6 receptor complexes with a STAT3 phosphorylation dominated activation profile | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=67650 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20241122-112014-7 | |||||||
| Kollektion: | Publikationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Texte » Artikel, Aufsatz | |||||||
| Medientyp: | Text | |||||||
| Autoren: | Seibel, Christiane [Autor] Pudewell, Silke [Autor] Rafii, Puyan [Autor] Ettich, Julia [Autor] Weitz, Hendrik T. [Autor] Lang, Alexander [Autor] Petzsch, Patrick [Autor] Floss, Doreen M. [Autor] Scheller, Jürgen [Autor] | |||||||
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| Stichwörter: | Interleukin 6, gp130, Janus kinase, synthetic cytokine biology | |||||||
| Beschreibung: | In Interleukin (IL)-6 signalling, IL-6 site I binds to the IL-6 receptor (IL-6R) first, following by IL-6 site II interaction to domain 2/3 of gp130 to form premature trimeric IL-6:IL–6R:gp130 receptor complexes. Formation of the mature hexameric receptor complex is then facilitated by the inter-trimeric interaction of IL-6 site III with domain 1 of the opposing gp130. The two gp130-associated Janus kinases (JAKs) trans-phosphorylate when their spatiotemporal pairing is correct, which causes the activation of STAT, ERK, and AKT pathways in a balanced manner. Since the intracellular domain (ICD) of IL-6R is not needed for STAT/ERK/AKT phosphorylation, we investigated the conditions under which a chimeric IL-6RECD-gp130TMD/ICD receptor protein confers biological activity. For IL–6RECD–gp130TMD/ICD, the extracellular domain (ECD) of IL-6R was fused to the transmembrane domain (TMD) and ICD of gp130. Co-expression of IL–6RECD–gp130TMD/ICD with signalling-deficient gp130 variants did not induce IL-6 signalling, suggesting that the assembly of hexameric complexes failed to dimerize the IL-6R-associated JAKs correctly. By mimicking the premature trimeric receptor complex, IL-6-mediated dimerization of IL-6RECD-gp130TMD/ICD with the single-cytokine-binding variant gp130ΔD1 induced signalling. Of note, IL-6 signalling via these synthetic gp130ΔD1:IL-6RECD-gp130TMD/ICD complexes resulted predominantly in STAT3 phosphorylation. A STAT3-dominated profile was also observed after IL-6-induced signalling mediated by a JAK-deficient IL–6RECD–gp130TMD/ICDΔJAK variant in complex with the JAK-proficient but STAT/ERK/AKT-deficient gp130JAKΔICD variant. Our data showed that effective ERK/AKT signalling could not be executed after intracellular domain swapping from gp130 to the IL-6R. Taken together, the chimeric IL-6R/gp130 receptor may be helpful in the creation of customized synthetic IL-6 signalling. | |||||||
| Rechtliche Vermerke: | Originalveröffentlichung:
Seibel, C., Pudewell, S., Rafii, P., Ettich, J., Weitz, H. T., Lang, A., Petzsch, P., Köhrer, K., Floß, D. M., & Scheller, J. (2024). Synthetic trimeric interleukin-6 receptor complexes with a STAT3 phosphorylation dominated activation profile. Cytokine, 184, Article 156766. https://doi.org/10.1016/j.cyto.2024.156766 | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 22.11.2024 | |||||||
| Dateien geändert am: | 22.11.2024 |
