Article
- The EMBO Journal (2007) 26, 3910 - 3922
- doi:10.1038/sj.emboj.7601823
Published online: 16 August 2007
Subject Category:
Essential role for TAX1BP1 in the termination of TNF-
-, IL-1- and LPS-mediated NF-
B and JNK signaling
Noula Shembade1, Nicole S Harhaj1, Daniel J Liebl2 and Edward W Harhaj1
- Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, FL, USA
- The Miami Project to Cure Paralysis and Department of Neurosurgery, Miller School of Medicine, The University of Miami, Miami, FL, USA
Correspondence to:
Edward W Harhaj, Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, 1550 NW 10 Avenue, Miami, FL 33136, USA. Tel.: +1 305 243 7893; Fax: +1 305 243 6410; E-mail: eharhaj@med.miami.edu
Received 27 February 2007; Accepted 19 July 2007
Abstract
The NF-
B transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-B activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-
- and LPS-mediated NF-B signaling by inactivating key signaling molecules. However, little is known about how A20 is regulated and if other molecules play a role in the termination of NF-B signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-B and JNK activation in response to TNF-, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF--, IL-1- and LPS-mediated IKK and JNK activation is elevated and persistent owing to enhanced ubiquitination of RIP1 and TRAF6. Furthermore, in the absence of TAX1BP1, A20 is impaired in RIP1 binding, deubiquitination of TRAF6 and inhibition of NF-B activation. Thus, TAX1BP1 is pivotal for the termination of NF-B and JNK signaling by functioning as an essential regulator of A20.
Keywords:
- A20,
- Tax,
- NF-B,
- RIP1,
- TAX1BP1,
- TRAF6
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