A molecular dissection of lymphocyte unresponsiveness induced by sustained calcium signalling.
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.
Department of Pathology, Harvard Medical School, CBR Institute for Biomedical Research, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Vigo
V
Heissmeyer
Fernando
F
Macián
Rajat
R
Varma
Sin-Hyeog
SH
Im
Francisco
F
García-Cozar
Heidi F
HF
Horton
Michael C
MC
Byrne
Stefan
S
Feske
K
K
Venuprasad
Hua
H
Gu
Yun-Cai
YC
Liu
Michael L
ML
Dustin
Anjana
A
Rao
D020013:Calcium Signaling; D017635:Clonal Anergy; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors