Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

TY - JOUR

T1 - Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

AU - Martinez-Fabregas, Jonathan

AU - Wilmes, Stephan

AU - Wang, Luopin

AU - Hafer, Maximillian

AU - Pohler, Elizabeth

AU - Lokau, Juliane

AU - Garbers, Christoph

AU - Cozzani, Adeline

AU - Piehler, Jacob

AU - Kazemian, Majid

AU - Mitra, Suman

AU - Moraga Gonzalez, Ignacio

N1 - We thank members of the Moraga, Mitra and Kazemian laboratories for helpful advice and discussion. We thank Dynamic Biosensors for their help characterizing IL-6 variants binding properties. This work was supported by the StG, LS6, Wellcome-Trust-202323/Z/16/Z and ERC-206-STG grant (I.M. J.M.F.), by EMBO (S.W. 454-2017) and by the DFG (SFB 944, P8/Z, J.P.)

PY - 2019/11/27

Y1 - 2019/11/27

N2 - 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.

AB - 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.

KW - bias signaling

KW - cytokine engineering

KW - cytokine signaling

KW - endosomal traffic

KW - functional pleiotropy

KW - human

KW - immunology

KW - inflammation

UR - https://www.scopus.com/pages/publications/85076585567

U2 - 10.7554/eLife.49314

DO - 10.7554/eLife.49314

M3 - Article

C2 - 31774398

SN - 2050-084X

VL - 8

SP - 1

EP - 32

JO - eLife

JF - eLife

M1 - e49314

ER -