Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses

William W. Reiley, Wei Jin, Andrew Joon Lee, Ato Wright, Xuefeng Wu, Eric F. Tewalt, Timothy O. Leonard, Christopher C. Norbury, Leo Fitzpatrick, Minying Zhang, Shao Cong Sun

Research output: Contribution to journalArticlepeer-review

207 Scopus citations

Abstract

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-β-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 IκB kinase β. 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. JEM

Original languageEnglish (US)
Pages (from-to)1475-1485
Number of pages11
JournalJournal of Experimental Medicine
Volume204
Issue number6
DOIs
StatePublished - Jun 11 2007

All Science Journal Classification (ASJC) codes

  • General Medicine

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