Membrane microdomains and cytoskeleton organization shape and regulate the IL-7 receptor signalosome in human CD4 T-cells

Tamarit, Blanche, Bugault, Florence, Pillet, Anne-Hélène, Lavergne, Vincent, Bochet, Pascal, Garin, Nathalie, Schwarz, Ulf, Theze, Jacques and Rose, Thierry (2013) Membrane microdomains and cytoskeleton organization shape and regulate the IL-7 receptor signalosome in human CD4 T-cells. Journal of Biological Chemistry, 288 12: 8691-8701. doi:10.1074/jbc.M113.449918

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Author Tamarit, Blanche
Bugault, Florence
Pillet, Anne-Hélène
Lavergne, Vincent
Bochet, Pascal
Garin, Nathalie
Schwarz, Ulf
Theze, Jacques
Rose, Thierry
Title Membrane microdomains and cytoskeleton organization shape and regulate the IL-7 receptor signalosome in human CD4 T-cells
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2013-03
Year available 2013
Sub-type Article (original research)
DOI 10.1074/jbc.M113.449918
Open Access Status File (Publisher version)
Volume 288
Issue 12
Start page 8691
End page 8701
Total pages 11
Place of publication Bethesda, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2014
Formatted 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 signaling 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 min 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 signaling complex, the signalosome, on the IL-7 receptor cytoplasmic domains. Here we describe by stimulated emission depletion microscopy the key roles played by membrane microdomains and cytoskeleton transient organization in the IL-7-regulated JAK/STAT signaling 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 the 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 2 min after IL-7 stimulation. Radial microtubules disappear 15 min later, while transversal microtubules, independent of phospho- STAT5 transport, begin to bud from the microtubule organization center.
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Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
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Created: Thu, 28 Nov 2013, 14:48:15 EST by System User on behalf of Institute for Molecular Bioscience