Synthetic trimeric interleukin-6 receptor complexes with a STAT3 phosphorylation dominated activation profile.

Autor: Seibel C; Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany., Pudewell S; Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany., Rafii P; Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany., Ettich J; Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany., Weitz HT; Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany., Lang A; Cardiovascular Research Laboratory, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany., Petzsch P; Biological and Medical Research Center (BMFZ), Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany., Köhrer K; Biological and Medical Research Center (BMFZ), Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany., Floss DM; Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany., Scheller J; Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany. Electronic address: jscheller@uni-duesseldorf.de.
Jazyk: angličtina
Zdroj: Cytokine [Cytokine] 2024 Dec; Vol. 184, pp. 156766. Date of Electronic Publication: 2024 Sep 29.
DOI: 10.1016/j.cyto.2024.156766
Abstrakt: 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-6R ECD -gp130 TMD/ICD receptor protein confers biological activity. For IL-6R ECD -gp130 TMD/ICD , the extracellular domain (ECD) of IL-6R was fused to the transmembrane domain (TMD) and ICD of gp130. Co-expression of IL-6R ECD -gp130 TMD/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-6R ECD -gp130 TMD/ICD with the single-cytokine-binding variant gp130 ΔD1 induced signalling. Of note, IL-6 signalling via these synthetic gp130 ΔD1 :IL-6R ECD -gp130 TMD/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-6R ECD -gp130 TMD/ICDΔJAK variant in complex with the JAK-proficient but STAT/ERK/AKT-deficient gp130 JAKΔICD 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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