title: Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses.
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-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.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Reiley
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Andrew Joon
authors.initials: AJ
authors.lastname: Lee
authors.forename: Ato
authors.initials: A
authors.lastname: Wright
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.forename: Eric F
authors.initials: EF
authors.lastname: Tewalt
authors.forename: Timothy O
authors.initials: TO
authors.lastname: Leonard
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Norbury
authors.forename: Leo
authors.initials: L
authors.lastname: Fitzpatrick
authors.forename: Minying
authors.initials: M
authors.lastname: Zhang
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: 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
chemical_list: D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7; C511601:CYLD protein, mouse