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R-Induced Actin Polymerization1
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* Department of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Epalinges, Switzerland;
Department of Clinical Pathology, Centre Medical Universitaire, Geneva, Switzerland;
Institut Cochin, Département de Biologie Cellulaire, Paris, France;
Institut National de la Santé et de la Recherche Médicale Unité 567, Paris, France;
¶ Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Paris, France;
|| Université Paris 5, Faculté de Médecine René Descartes, Paris, France;
# Institute for Research in Biomedicine, Bellinzona, Switzerland,
** Third Medical Department, Technical University of Munich, Klinikum Rechts der Isar, Munich, Germany; and
The Campbell Family Institute for Breast Cancer Research and Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
Bcl10 plays an essential role in the adaptive immune response, because Bcl10-deficient lymphocytes show impaired Ag receptor-induced NF-
B activation and cytokine production. Bcl10 is a phosphoprotein, but the physiological relevance of this posttranslational modification remains poorly defined. In this study, we report that Bcl10 is rapidly phosphorylated upon activation of human T cells by PMA/ionomycin- or anti-CD3 treatment, and identify Ser138 as a key residue necessary for Bcl10 phosphorylation. We also show that a phosphorylation-deficient Ser138/Ala mutant specifically inhibits TCR-induced actin polymerization yet does not affect NF-B activation. Moreover, silencing of Bcl10, but not of caspase recruitment domain-containing MAGUK protein-1 (Carma1) induces a clear defect in TCR-induced F-actin formation, cell spreading, and conjugate formation. Remarkably, Bcl10 silencing also impairs Fc
R-induced actin polymerization and phagocytosis in human monocytes. These results point to a key role of Bcl10 in F-actin-dependent immune responses of T cells and monocytes/macrophages.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Swiss Cancer League (to M.Tho. and J.S.), Swiss National Science Foundation (to M.Tho. and J.S.), and Cancer and Solidarité (to J.S.). F.N. is supported by grants from the Ville de Paris and Centre National de la Recherche Scientifique (Action Thématique d’Intérêt Prioritaire Jeune Chercheur Microbiologie). J.R. is supported by a Max-Eder-Program Grant from Deutsche Krebshilfe and by grants from Deutsche Forschungsgemeinschaft. O.G. was supported by a M.D.-PhD fellowship from the Swiss Academy of Medical Sciences. D.R. was supported by a postdoctoral fellowship from the Spanish Ministry of Education and Science. S.H. was supported by a PhD fellowship from the Studienstiftung des Deutschen Volkes. E.L. was supported by a Bourse de Docteur Ingénieur du Centre National de la Recherche Scientifique.
2 O.G. and L.H. contributed equally to this study.
3 Current address: University Medical Center, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland.
4 Current address: Department of Research, University Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland.
5 Address correspondence and reprint requests to Dr. Margot Thome, Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, Epalinges, Switzerland. E-mail address: Margot.ThomeMiazza{at}unil.ch
6 Abbreviations used in this paper: MALT, mucosa-associated lymphoid tissue; CARD, caspase recruitment domain; Carma1, CARD-containing MAGUK protein-1; IKK, IB kinase; Malt1, MALT lymphoma translocation protein-1; GEF, GDP/GTP exchange factor; WASP, Wiskott-Aldrich syndrome protein; siRNA, small interfering RNA; shRNA, short hairpin RNA; EGFP, enhanced GFP; IgG-SRBC, IgG-coated SRBC; wt, wild type; PKC, protein kinase C; DN, dominant negative; RIP, receptor-interacting protein; SEE, staphylococcal enterotoxin E.
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