title: Protein kinase C-δ negatively regulates T cell receptor-induced NF-κB activation by inhibiting the assembly of CARMA1 signalosome.
abstract: T-cell receptor (TCR)-induced T-cell activation is a critical event in adaptive immune responses. The engagement of TCR complex by antigen along with the activation of the costimulatory receptors trigger a cascade of intracellular signaling, in which caspase recruitment domain-containing membrane-associated guanylate kinase 1 (CARMA1) is a crucial scaffold protein. Upon stimulation, CARMA1 recruits downstream molecules including B-cell CLL/lymphoma 10 (Bcl10), mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1), and TRAF6 to assemble a specific TCR-induced signalosome that triggers NF-κB and JNK activation. In this report, we identified protein kinase Cδ (PKCδ) as a CARMA1-associated protein by a biochemical affinity purification approach. PKCδ interacted with CARMA1 in TCR stimulation-dependent manner in Jurkat T cells. Overexpression of PKCδ inhibited CARMA1-mediated NF-κB activation, whereas knockdown of PKCδ potentiated TCR-triggered NF-κB activation and IL-2 secretion in Jurkat T cells. Reconstitution experiments with PKCδ kinase-dead mutant indicated that the kinase activity of PKCδ was dispensable for its ability to inhibit TCR-triggered NF-κB activation. Furthermore, we found that PKCδ inhibited the interaction between MALT1 and TRAF6, but not the association of CARMA1 with PKCθ, Bcl10, or MALT1. These observations suggest that PKCδ is a negative regulator in T cell activation through inhibiting the assembly of CARMA1 signalosome.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China. yuliu@whu.edu.cn
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Ren
authors.initials: R
authors.lastname: Song
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yun-Hong
authors.initials: YH
authors.lastname: Hu
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000201:enzymology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; C508594:IL2 protein, human; D007376:Interleukin-2; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D048029:TNF Receptor-Associated Factor 6; D051745:Protein Kinase C-delta; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase