title: Transient PKCα shuttling to the immunological synapse is governed by DGKζ and regulates L-selectin shedding.
abstract: Considerable evidence indicates that diacylglycerol (DAG) generation at the immunological synapse (IS) determines T cell functions by regulating the duration and amplitude of Ras/ERK signals. The exact mechanism by which DAG regulates Ras/ERK activation downstream of the T cell receptor (TCR) nonetheless remains poorly understood. Here we characterize PKCα as a previously unrecognized component of the machinery that translates cell receptor occupancy into Ras/ERK-propagated signals. We show transient translocation of PKCα to the IS, mediated by DAG generation at the contact area. Diacylglycerol kinase (DGK)ζ negatively regulated PKCα translocation kinetics, whereas PKCα activity limited its own persistence at the IS. Coordinated activation of DGKζ and PKCα in response to antigen recognition regulated the amplitude and duration of Ras/ERK activation; this in turn mediated early processes of T cell surface proteolysis such as L-selectin shedding. Analysis of DGKζ-deficient mice further showed that increased DAG signaling is translated to downstream elements of this pathway, as reflected by enhanced PKCα-dependent L-selectin shedding. We propose that early activation of a DAG-PKCα axis contributes to the mechanisms by which antigen affinity translates into TCR biological responses.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas (CNB/CSIC), 28049 Madrid, Spain. sgharbi@cnb.csic.es
authors.forename: Severine I
authors.initials: SI
authors.lastname: Gharbi
authors.forename: Antonia
authors.initials: A
authors.lastname: Avila-Flores
authors.forename: Denise
authors.initials: D
authors.lastname: Soutar
authors.forename: Ana
authors.initials: A
authors.lastname: Orive
authors.forename: Gary A
authors.initials: GA
authors.lastname: Koretzky
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Albar
authors.forename: Isabel
authors.initials: I
authors.lastname: Mérida
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism*; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism*; D019169:Jurkat Cells; D019041:L-Selectin / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000941:Antigens; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D019041:L-Selectin; C526464:DGKE protein, human; D019852:Diacylglycerol Kinase; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D015689:Oncogene Protein p21(ras)
keywords: Diacylglycerol kinase; Immune synapse; Protein kinase C