期刊
CELL COMMUNICATION AND SIGNALING
卷 13, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/s12964-015-0100-3
关键词
T lymphocyte signaling; Transcriptional regulation; Protein kinase C theta (PKC theta); Coronin 1A (Coro1A); NF-kappa B; IL-2
类别
资金
- FWF Austrian Science Fund [25044-B21, M1636-B23]
- Medical University Innsbruck for young scientists MUI-START [2013042002]
- Austrian Science Fund (FWF) [M 1636, P 25044] Funding Source: researchfish
- Austrian Science Fund (FWF) [M1636] Funding Source: Austrian Science Fund (FWF)
Background: Protein kinase C-theta (PKC theta) plays an important role in signal transduction down-stream of the T cell receptor and T cells deficient of PKC theta show impaired NF-kappa B as well as NFAT/AP-1 activation resulting in strongly decreased IL-2 expression and proliferation. However, it is not yet entirely clear, how the function of PKC theta - upon T cell activation -is regulated on a molecular level. Findings: Employing a yeast two-hybrid screen and co-immunoprecipitation analyses, we here identify coronin 1A (Coro1A) as a novel PKC theta-interacting protein. We show that the NH2-terminal WD40 domains of Coro1A and the C2-like domain of PKC theta are sufficient for the interaction. Furthermore, we confirm a physical interaction by GST-Coro1A mediated pull-down of endogenous PKC theta protein. Functionally, wild-type but not Coro1A lacking its actin-binding domain negatively interferes with PKC theta-dependent NF-kappa B, Cyclin D1 and IL-2 transactivation when analysed with luciferase promoter activation assays in Jurkat T cells. This could be phenocopied by pharmacological inhibitors of actin polymerization and PKC, respectively. Mechanistically, Coro1A overexpression attenuates both lipid raft and plasma membrane recruitment of PKC theta in CD3/CD28-activated T cells. Using primary CD3(+) T cells, we observed that (opposite to PKC theta) Coro1A does not localize preferentially to the immunological synapse. In addition, we show that CD3(+) T cells isolated from Coro1A-deficient mice show impaired IKK/NF-kappa B transactivation. Conclusions: Together, these findings both in Jurkat T cells as well as in primary T cells indicate a regulatory role of Coro1A on PKC theta recruitment and function downstream of the TCR leading to NF-kappa B transactivation.
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