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PMID:14973438
| Citation |
Heissmeyer, V, Macián, F, Im, SH, Varma, R, Feske, S, Venuprasad, K, Gu, H, Liu, YC, Dustin, ML and Rao, A (2004) Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat. Immunol. 5:255-65 |
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| Abstract |
Sustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca(2+)-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC-theta and PLC-gamma1. T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte function-associated antigen 1. Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells. |
| Links |
PubMed Online version:10.1038/ni1047 |
| Keywords |
Animals; Calcineurin/physiology; Calcium Signaling; Cells, Cultured; Clonal Anergy; DNA-Binding Proteins/biosynthesis; DNA-Binding Proteins/genetics; Endosomal Sorting Complexes Required for Transport; Isoenzymes/metabolism; Mice; Mice, Inbred BALB C; Phospholipase C gamma; Protein Kinase C/metabolism; RNA, Messenger/biosynthesis; T-Lymphocytes/immunology; T-Lymphocytes/metabolism; Transcription Factors/biosynthesis; Transcription Factors/genetics; Type C Phospholipases/metabolism; Ubiquitin-Protein Ligases/biosynthesis; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Ubiquitins/metabolism; Up-Regulation |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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