Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD.
The IkappaB kinase (IKK)-related kinases, IKKepsilon and TBK1, participate in the induction of type I interferons (IFNs) during viral infections. Deregulated activation of IKKepsilon and TBK1 also contributes to the abnormal cell survival and transformation. However, how these kinases are negatively regulated remains unclear. We show here that the tumor suppressor CYLD has an essential role in preventing aberrant activation of IKKepsilon/TBK1. CYLD deficiency causes constitutive activation of IKKepsilon/TBK1, which is associated with hyper-induction of IFNs in virus-infected cells. We further show that CYLD targets a cytoplasmic RNA sensor, RIG-I, and inhibits the ubiquitination of this IKKepsilon/TBK1 stimulator. Consistent with the requirement of ubiquitination in RIG-I function, CYLD potently inhibits RIG-I-mediated activation of the IFN-beta promoter. These findings establish CYLD as a key negative regulator of IKKepsilon/TBK1 and suggest a role for CYLD in the control of RIG-I ubiquitination.
Zhang
Minying
M
Department of Immunology, the University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Wu
Xuefeng
X
Lee
Andrew J
AJ
Jin
Wei
W
Chang
Mikyoung
M
Wright
Ato
A
Imaizumi
Tadaatsu
T
Sun
Shao-Cong
SC
D000818:Animals; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation / Q000235:genetics; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics; D014777:Virus Diseases / Q000235:genetics / Q000378:metabolism*; D000097905:Roundabout Proteins
D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D051550:I-kappa B Kinase; D016899:Interferon-beta; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C498588:Tbk1 protein, mouse; C511601:CYLD protein, mouse