Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 204, Issue 6, Pages 1475-1485Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20062694
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Funding
- NCI NIH HHS [CA94922, T32 CA060395, R01 CA094922, 2T32CA60395-11] Funding Source: Medline
- NCRR NIH HHS [C06 RR015428, C06 RR-15428-01] Funding Source: Medline
- NIAID NIH HHS [AI056094, R01 AI056094, AI064639, R01 AI057555, AI057555, R56 AI056094, R37 AI064639, R01 AI064639] Funding Source: Medline
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The deubiquitinating enzyme CYLD has recently been implicated in the regulation of signal transduction, but its physiological function and mechanism of action are still elusive. In this study, we show that CYLD plays a pivotal role in regulating T cell activation and homeostasis. T cells derived from Cyld knockout mice display a hyperresponsive phenotype and mediate the spontaneous development of intestinal inflammation. Interestingly, CYLD targets a ubiquitin- dependent kinase, transforming growth factor-beta-activated kinase 1 (Tak1), and inhibits its ubiquitination and autoactivation. Cyld-deficient T cells exhibit constitutively active Tak1 and its downstream kinases c-Jun N-terminal kinase and I kappa B kinase beta. These results emphasize a critical role for CYLD in preventing spontaneous activation of the Tak1 axis of T cell signaling and, thereby, maintaining normal T cell function.
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