The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response.
On detecting viral RNAs, the RNA helicase retinoic acid-inducible gene I (RIG-I) activates the interferon regulatory factor 3 (IRF3) signalling pathway to induce type I interferon (IFN) gene transcription. How this antiviral signalling pathway might be negatively regulated is poorly understood. Microarray and bioinformatic analysis indicated that the expression of RIG-I and that of the tumour suppressor CYLD (cylindromatosis), a deubiquitinating enzyme that removes Lys 63-linked polyubiquitin chains, are closely correlated, suggesting a functional association between the two molecules. Ectopic expression of CYLD inhibits the IRF3 signalling pathway and IFN production triggered by RIG-I; conversely, CYLD knockdown enhances the response. CYLD removes polyubiquitin chains from RIG-I as well as from TANK binding kinase 1 (TBK1), the kinase that phosphorylates IRF3, coincident with an inhibition of the IRF3 signalling pathway. Furthermore, CYLD protein level is reduced in the presence of tumour necrosis factor and viral infection, concomitant with enhanced IFN production. These findings show that CYLD is a negative regulator of RIG-I-mediated innate antiviral response.
Friedman
Constantin S
CS
Immunology Institute, Mount Sinai School of Medicine, Box 1630, One Gustave L Levy Place, New York, New York 10029, USA.
O'Donnell
Marie Anne
MA
Legarda-Addison
Diana
D
Ng
Aylwin
A
Cárdenas
Washington B
WB
Yount
Jacob S
JS
Moran
Thomas M
TM
Basler
Christopher F
CF
Komuro
Akihiko
A
Horvath
Curt M
CM
Xavier
Ramnik
R
Ting
Adrian T
AT
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D016000:Cluster Analysis; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D009154:Mutation; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D029082:Sendai virus / Q000502:physiology; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells
D048868:Adaptor Proteins, Signal Transducing; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C505371:MAVS protein, human; D011971:Receptors, Immunologic; D025521:Tumor Suppressor Proteins; D025821:Polyubiquitin; D007372:Interferons; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases