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Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL7-Receptor Signalosome in Human CD4 T-Cells

Abstract : Interleukin(IL)-7 is the main homeostatic regulator of CD4 T-lymphocytes (helper) at both central and peripheral levels. Upon activation by IL-7, several signalling pathways, mainly Jak/STAT, PI3K/Akt and MAPK, induce the expression of genes involved in T-cell differentiation, activation and proliferation. We have analyzed the early events of CD4 T-cell activation by IL-7. We have shown that IL-7 in the first few minutes induces the formation of cholesterol-enriched membrane microdomains that compartmentalize its activated receptor and initiate its anchoring to the cytoskeleton supporting the formation of the signalling complex-the signalosome-on the IL-7-receptor cytoplasmic-domains. Here we describe by stimulated emission depletion (STED) microscopy, the key roles played by membrane microdomains and cytoskeleton transient organization in the IL-7-regulated Jak/STAT signalling pathway. We image phospho-STAT5 and cytoskeleton components along IL-7-activation kinetics using appropriate inhibitors. We show that lipid raft inhibitors delay and reduce IL-7-induced Jak1 and Jak3 phosphorylation. Drug-induced disassembly of cytoskeleton inhibits phospho-STAT5 formation, transport and translocation into the nucleus that controls the transcription of genes involved in T-cell activation and proliferation. We fit together the results of these quantitative analyses and propose the following mechanism: activated IL-7-receptors embedded in membrane microdomains induce actin-microfilament meshwork formation, anchoring microtubules that grow radially from rafted receptors to the nuclear membrane. STAT5 phosphorylated by signalosomes are loaded on kinesins and glide along the microtubules across the cytoplasm to reach the nucleus two minutes after IL-7-stimulation. Radial microtubules disappear 15 minutes later while transversal microtubules, independent of phospho-STAT5 transport, begin to bud from the microtubule organization center.
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Submitted on : Friday, December 6, 2019 - 3:26:01 PM
Last modification on : Monday, January 13, 2020 - 5:08:16 PM

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Blanche Tamarit, Florence Bugault, Anne-Hélène Pillet, Vincent Lavergne, Pascal Bochet, et al.. Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL7-Receptor Signalosome in Human CD4 T-Cells. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2013, 288 (12), pp.8691 - 8701. ⟨10.1074/jbc.M113.449918⟩. ⟨pasteur-02397495⟩

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