Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses.
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 IkappaB 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.
Reiley
William W
WW
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Jin
Wei
W
Lee
Andrew Joon
AJ
Wright
Ato
A
Wu
Xuefeng
X
Tewalt
Eric F
EF
Leonard
Timothy O
TO
Norbury
Christopher C
CC
Fitzpatrick
Leo
L
Zhang
Minying
M
Sun
Shao-Cong
SC
D019264:Adoptive Transfer; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination / Q000276:immunology; D000099151:MAP Kinase Kinase Kinase 7
D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7; C511601:CYLD protein, mouse