Interleukin (IL)-7 is a central cytokine that controls homeostasis of the CD4 T lymphocyte pool. Here we show on human primary cells that IL-7 binds to preassembled receptors made up of proprietary chain IL-7R␣ and the common chain ␥c shared with IL-2, -4, -9, -15, and -21 receptors. Upon IL-7 binding, both chains are driven in cholesterol-and sphingomyelin-rich rafts where associated signaling proteins Jak1, Jak3, STAT1, -3, and -5 are found to be phosphorylated. Meanwhile the IL-7⅐IL-7R complex interacts with the cytoskeleton that halts its diffusion as measured by single molecule fluorescence autocorrelated spectroscopy monitored by microimaging. Comparative immunoprecipitations of IL-7R␣ signaling complex from non-stimulated and IL-7-stimulated cells confirmed recruitment of proteins such as STATs, but many others were also identified by mass spectrometry from two-dimensional gels. Among recruited proteins, two-thirds are involved in cytoskeleton and raft formation. Thus, early events leading to IL-7 signal transduction involve its receptor compartmentalization into membrane nanodomains and cytoskeleton recruitment.
Background: Interleukin-7 is the master regulator of T-cell proliferation. Results: IL-7 drives its receptor in a membrane microdomain that regulates phosphorylation of associated tyrosine kinases JAK1 and JAK3, anchors IL-7 receptor to cytoskeleton and regulates STAT5 phosphorylation and nuclear translocation. Conclusion: Membrane microdomains and cytoskeleton scaffold IL-7R-signalosomes and assist signaling protein transport. Significance: Transient membrane and cytoskeleton organization shapes IL-7-signaling mechanisms in CD4 T-cells.
In Fig. 5b, an incorrect image was used for Jak3. Fig. 6j did not indicate the borders between different sections of the same gel. Incorrect traces were used in Fig. S4. These errors have now been corrected and do not affect the results or conclusions of this work.
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