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| Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins |
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| Author(s): Heissmeyer V, Macian F, Im SH, Varma R, Feske S, Venuprasad K, Gu H, Liu YC, Dustin ML, Rao A |
| Source: NATURE IMMUNOLOGY Volume: 5 Issue: 3 Pages: 255-265 Published: MAR 2004 |
| Times Cited: 209 References: 51 |
| 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 Ca2+-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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Rao, A (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA |
Addresses:
1. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA
2. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
3. NYU, Sch Med, Program Mol Pathogenesis, New York, NY 10016 USA
4. NYU, Sch Med, Dept Pathol, Skirball Inst Mol Med, New York, NY 10016 USA
5. La Jolla Inst Allergy & Immunol, Div Cell Biol, San Diego, CA 92121 USA
6. Columbia Univ Coll Phys & Surg, Dept Microbiol, New York, NY 10032 USA |
| Publisher: NATURE PUBLISHING GROUP, 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA |
| Subject Category: Immunology |
| IDS Number: 779ZV |
| ISSN: 1529-2908 |
| DOI: 10.1038/ni1047 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |