A molecular dissection of lymphocyte unresponsiveness induced by sustained calcium signalling
| Autor: | Heissmeyer, Vigo, Macian, Fernando, Varma, Rajat, Im, Sin-Hyeog, Francisco Garcia-Cozar, Horton, Heidi F., Byrne, Michael C., Feske, Stefan, Venuprasad, K., Gu, Hua, Liu, Yun-Cai, Dustin, Michael L., Rao, Anjana |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Zdroj: | Scopus-Elsevier Europe PubMed Central ResearcherID |
| Popis: | In lymphocytes, integration of Ca2+ and other signalling pathways results in productive activation, while unopposed Ca2+ signalling leads to decreased responsiveness to subsequent stimulation (anergy). The Ca(2+)-regulated transcription factor NFAT has an integral role in both aspects of lymphocyte function. NFAT cooperates with the transcription factor AP-1 (Fos/Jun) to up-regulate genes involved in productive activation of lymphocytes. However, in the absence of AP-1, NFAT imposes an opposing genetic programme that leads to lymphocyte anergy. Anergy is implemented at least partly through proteolytic degradation of the key signalling proteins PKCtheta and PLCgamma1. Sustained Ca(2+)-calcineurin signalling increases mRNA and protein levels of the E3 ubiquitin ligases Itch, CblB and Grail and induces expression of Tsg1O1, the ubiquitin-binding component of the ESCRT1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promotes membrane translocation of Itch and the related protein Nedd4, resulting in PKCtheta and PLCgamma1 degradation. T cells from Itch- and CblB-deficient mice are resistant to anergy induction. Anergic T cells show impaired calcium mobilization after TCR triggering and are unable to maintain a mature immunological synapse. Thus Ca(2+)-calcineurin-NFAT signalling links gene transcription to a multi-step programme that leads to impaired signal transduction in anergic T cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|