title: PKCθ/β and CYLD are antagonistic partners in the NFκB and NFAT transactivation pathways in primary mouse CD3+ T lymphocytes.
abstract: In T cells PKCθ mediates the activation of critical signals downstream of TCR/CD28 stimulation. We investigated the molecular mechanisms by which PKCθ regulates NFκB transactivation by examining PKCθ/β single and double knockout mice and observed a redundant involvement of PKCθ and PKCβ in this signaling pathway. Mechanistically, we define a PKCθ-CYLD protein complex and an interaction between the positive PKCθ/β and the negative CYLD signaling pathways that both converge at the level of TAK1/IKK/I-κBα/NFκB and NFAT transactivation. In Jurkat leukemic T cells, CYLD is endoproteolytically processed in the initial minutes of stimulation by the paracaspase MALT1 in a PKC-dependent fashion, which is required for robust IL-2 transcription. However, in primary T cells, CYLD processing occurs with different kinetics and an altered dependence on PKC. The formation of a direct PKCθ/CYLD complex appears to regulate the short-term spatial distribution of CYLD, subsequently affecting NFκB and NFAT repressional activity of CYLD prior to its MALT1-dependent inactivation. Taken together, our study establishes CYLD as a new and critical PKCθ interactor in T cells and reveals that antagonistic PKCθ/β-CYLD crosstalk is crucial for the adjustment of immune thresholds in primary mouse CD3(+) T cells.
authors: Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors: Nikolaus
authors: N
authors: Thuille
authors: Katarzyna
authors: K
authors: Wachowicz
authors: Natascha
authors: N
authors: Hermann-Kleiter
authors: Sandra
authors: S
authors: Kaminski
authors: Friedrich
authors: F
authors: Fresser
authors: Christina
authors: C
authors: Lutz-Nicoladoni
authors: Michael
authors: M
authors: Leitges
authors: Margot
authors: M
authors: Thome
authors: Ramin
authors: R
authors: Massoumi
authors: Gottfried
authors: G
authors: Baier
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D017252:CD3 Complex; D020169:Caspases; D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D011493:Protein Kinase C; D000099151:MAP Kinase Kinase Kinase 7; C511601:CYLD protein, mouse; C498509:Malt1 protein, mouse