Kinetics of cytokine receptor trafficking determine signaling and functional selectivity.
Elife
; 82019 11 27.
Article
en En
| MEDLINE
| ID: mdl-31774398
ABSTRACT
Cytokines activate signaling via assembly of cell surface receptors, but it is unclear whether modulation of cytokine-receptor binding parameters can modify biological outcomes. We have engineered IL-6 variants with different affinities to gp130 to investigate how cytokine receptor binding dwell-times influence functional selectivity. Engineered IL-6 variants showed a range of signaling amplitudes and induced biased signaling, with changes in receptor binding dwell-times affecting more profoundly STAT1 than STAT3 phosphorylation. We show that this differential signaling arises from defective translocation of ligand-gp130 complexes to the endosomal compartment and competitive STAT1/STAT3 binding to phospho-tyrosines in gp130, and results in unique patterns of STAT3 binding to chromatin. This leads to a graded gene expression response and differences in ex vivo differentiation of Th17, Th1 and Treg cells. These results provide a molecular understanding of signaling biased by cytokine receptors, and demonstrate that manipulation of signaling thresholds is a useful strategy to decouple cytokine functional pleiotropy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Interleucina-6
/
Linfocitos T Reguladores
/
Células TH1
/
Factor de Transcripción STAT1
/
Receptor gp130 de Citocinas
/
Células Th17
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Elife
Año:
2019
Tipo del documento:
Article
País de afiliación:
Reino Unido