Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL7-Receptor Signalosome in Human CD4 T-Cells
| العنوان: | Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL7-Receptor Signalosome in Human CD4 T-Cells |
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| المؤلفون: | Jacques Thèze, Florence Bugault, Ulf Schwarz, Vincent Lavergne, Thierry Rose, Anne-Hélène Pillet, Blanche Tamarit, Pascal Bochet, Nathalie Garin |
| المساهمون: | Immunogénétique Cellulaire, Institut Pasteur [Paris], Cellule Pasteur UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris], Leica Microsystems CMS GmbH, We thank Dr. Andres Alcover and Dr. Rémi Lasserre (Institut Pasteur) for helpful discussions. We thank Pascal Roux and Emmanuelle Perret (Plate-Forme d'Imagerie Dynamique, Institut Pasteur) for expertise and technical help in microscopy and Mark Jones (Transcriptum) for text editing. We extend our gratitude to the volunteer blood donors and staff at the Etablissement Français du Sang (Centre Necker-Cabanel-Paris)., Institut Pasteur [Paris] (IP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP) |
| المصدر: | Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2013, 288 (12), pp.8691-8701. ⟨10.1074/jbc.M113.449918⟩ Journal of Biological Chemistry, 2013, 288 (12), pp.8691-8701. ⟨10.1074/jbc.M113.449918⟩ |
| بيانات النشر: | HAL CCSD, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, MESH: Signal Transduction, Cytoskeleton organization, receptor, MESH: Membrane Microdomains, MESH: Janus Kinase 1, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Lymphocyte Activation, Microtubules, Biochemistry, MESH: Janus Kinase 3, 0302 clinical medicine, STAT5 Transcription Factor, cytokine, Phosphorylation, signalling, Cytoskeleton, Lipid raft, Cells, Cultured, lipid rafts, 0303 health sciences, MESH: Kinetics, interleukin, MESH: Microtubules, STAT, microdomain, MESH: CD4-Positive T-Lymphocytes, cytoskeleton, Transport protein, Cell biology, STED, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Actin Cytoskeleton, Protein Transport, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Additions and Corrections, Signal transduction, Signal Transduction, MESH: Cells, Cultured, MESH: Cell Nucleus, Cholera Toxin, MESH: Protein Transport, MESH: Receptors, Interleukin-7, human CD4 T cell, Biology, 03 medical and health sciences, Membrane Microdomains, Microtubule, MESH: Cell Proliferation, MESH: Cytoskeleton, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Lymphocyte Activation, Molecular Biology, PI3K/AKT/mTOR pathway, MESH: Cholera Toxin, Cell Proliferation, 030304 developmental biology, Cell Nucleus, Receptors, Interleukin-7, IL-7, MESH: Humans, MESH: Phosphorylation, MESH: STAT5 Transcription Factor, Janus Kinase 3, Janus Kinase 1, Cell Biology, Actin cytoskeleton, human CD4 T-cell, Jak, Kinetics, MESH: Protein Processing, Post-Translational, MESH: Actin Cytoskeleton, Protein Processing, Post-Translational, 030215 immunology |
| الوصف: | International audience; 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. |
| اللغة: | English |
| تدمد: | 0021-9258 1083-351X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ae84103c33230a84c84999f2b220684e https://hal-pasteur.archives-ouvertes.fr/pasteur-02397495 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ae84103c33230a84c84999f2b220684e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00219258 1083351X |
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