Receptor dimer stabilization by hierarchical plasma membrane microcompartments regulates cytokine signaling

You, Changjiang; Marquez‐Lago, Tatiana T.; Richter, Christian; Wilmes, Stephan; Moraga, Ignacio; García, K. Christopher; Leier, André; Piehler, Jacob

doi:10.1126/sciadv.1600452

Cited by 36 publications

(43 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8d), allowing to maintain signalling activity in early endosomes as specifically demonstrated for the IL-4 receptor2531. Thus, rather than being relevant for pre-organization of receptor subunits, our results support the emerging role of plasma membrane microcompartmentalization in sustaining signalling complexes, once they have formed, by passive confinement4752.…”

Section: Discussionsupporting

confidence: 76%

“…This model corroborates the hypothesis that passive confinement by the MSK ensures rapid re-association of transient receptor dimers. While cholesterol depletion experiments suggest that lipid-based segregation does not significantly contribute to receptor dimerization, MSK-dependent hierarchical TCZ as observed by recent single particle tracking studies with very high spatiotemporal resolution4952 may further enhance this effect and thus explain the residual discrepancies between experimental and simulated data. However, rather than shifting the equilibrium by local enrichment of the interaction partners, MSK-based TCZs ensure rapid re-association of the same receptor subunits.…”

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments

et al. 2017

Self Cite

View full text Add to dashboard Cite

The spatiotemporal organization of cytokine receptors in the plasma membrane is still debated with models ranging from ligand-independent receptor pre-dimerization to ligand-induced receptor dimerization occurring only after receptor uptake into endosomes. Here, we explore the molecular and cellular determinants governing the assembly of the type II interleukin-4 receptor, taking advantage of various agonists binding the receptor subunits with different affinities and rate constants. Quantitative kinetic studies using artificial membranes confirm that receptor dimerization is governed by the two-dimensional ligand–receptor interactions and identify a critical role of the transmembrane domain in receptor dimerization. Single molecule localization microscopy at physiological cell surface expression levels, however, reveals efficient ligand-induced receptor dimerization by all ligands, largely independent of receptor binding affinities, in line with the similar STAT6 activation potencies observed for all IL-4 variants. Detailed spatiotemporal analyses suggest that kinetic trapping of receptor dimers in actin-dependent microcompartments sustains robust receptor dimerization and signalling.

show abstract

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 92%

Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Single molecule localization and single molecule tracking were carried out using the multipletarget tracing (MTT) algorithm (Serge et al, 2008) as described previously (You et al, 2016).…”

Section: Live-cell Dual-color Single-molecule Imaging Studiesmentioning

confidence: 99%

Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

Martínez-Fábregas

Wilmes

Wang

et al. 2019

Preprint

View full text Add to dashboard Cite

Cytokines activate downstream signaling networks via assembly of cell surface receptors, but it is unclear whether modulation of cytokine-receptor binding parameters can modify biological outcomes. We have engineered variants of IL-6 with different affinities to the gp130 receptor chain to investigate how cytokine receptor binding kinetics influence functional selectivity. Engineered IL-6 variants showed a range of signaling amplitudes, from minimal to full agonist, and induced biased signaling, with changes in receptor binding kinetics 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, in turn, leads to a graded gene expression response and substantial 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.

show abstract

“…Since the actin network fluctuates and changes as well as the internal section of the receptors, it is expected that these domains will diffuse and change in time on a longer timescale. This interpretation is supported by the high protein density in the plasma membrane and the many reports that implicate that the cortical actin network plays a role in restricting protein motion in the cell membrane (for example 6,48,50-55 ). Moreover, studies of the structure of the actin cortex 6,56 show that the actin mesh size in comparable to the length scale emerging form our various measurement for domain size and flow suppression, i.e.…”

Section: Discussionmentioning

confidence: 85%

“…How these factors affect and contribute to optimize sensing and signaling at the interface between a cell and its surrounding is still not fully understood. However, some studies hint that the passive receptor confinement in microcompartments of the plasma membrane may promote the maintenance of signaling protein complexes 55 . We hypothesize that the correlated motion of proteins within these compartments may add to the integrity of such complexes without affecting proteins at larger distances.…”

Section: Discussionmentioning

confidence: 99%

Flow arrest in the plasma membrane

Chein

Perlson

Roichman

2019

Preprint

View full text Add to dashboard Cite

The arrangement of receptors in the plasma membrane strongly affects the ability of a cell to sense its environment both in terms of sensitivity and in terms of spatial resolution. The spatial and temporal arrangement of the receptors is affected in turn by the mechanical properties and the structure of the cell membrane. Here we focus on characterizing the flow of the membrane in response to the motion of a protein embedded in it. We do so by measuring the correlated diffusion of extracellularly tagged transmembrane neurotrophin receptors TrkB and p75 on transfected neuronal cells. In accord with previous reports, we find that the motion of single receptors exhibits transient confinement to sub-micron domains. We confirm predictions based on hydrodynamics of fluid membranes, finding long-range correlations in the motion of the receptors in the plasma membrane. However, we discover that these correlations do not persist for long ranges, as predicted, but decay exponentially, with a typical decay length on the scale of the average confining domain size.

show abstract

Receptor dimer stabilization by hierarchical plasma membrane microcompartments regulates cytokine signaling

Abstract: Single-molecule tracking and spatial stochastic modeling reveal receptor dimer stabilization by nanoscale confinement zones.

Cited by 36 publications

References 74 publications

Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments

Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments

Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

Flow arrest in the plasma membrane

Contact Info

Product

Resources

About