Article

Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappa B and JNK signaling

Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, FL 33136, USA.
The EMBO Journal (Impact Factor: 10.75). 10/2007; 26(17):3910-22. DOI: 10.1038/sj.emboj.7601823
Source: PubMed

ABSTRACT The NF-kappaB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-kappaB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-alpha- and LPS-mediated NF-kappaB 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-kappaB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-kappaB and JNK activation in response to TNF-alpha, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-alpha-, 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-kappaB activation. Thus, TAX1BP1 is pivotal for the termination of NF-kappaB and JNK signaling by functioning as an essential regulator of A20.

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    • "Notably, A20 deubiquitinating enzyme, which belongs to the same deubiquitinase family (OTU family) as VCIP135, has a binding protein, TAX1BP1 (Shembade et al, 2010). TAX1BP1 interacts with ubiquitinated substrates and recognizes their polyubiquitin chains (Shembade et al, 2007; VCIP135 and WAC in p97-mediated membrane fusion G Totsukawa et al "
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    • "Additionally, multiple modulatory components in Tax-mediated NF-κB activation have been newly identified, suggesting this signaling could be more complex than originally thought. For example, Tax1 binding protein, TAX1BP1, was demonstrated to be involved in the recruitment of A20 deubiquitinase for termination of NF-κB signaling, and Tax may target TAX1BP1 to counteract the function of A20 and promote persistent NF-κB activation (Iha et al., 2008; Shembade et al., 2007a, 2007b). Also, Pin1, a cellular isomerase, was found to target phosphorylated Tax and be critical for Tax binding to IKKγ and its subsequent activation of the NF-κB pathway (Peloponese et al., 2009). "
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    • "The PPXY motif could bind directly to the Itch WW domain, and one of the functions of RNF11 may be to facilitate Itch ubiquitination of specific target proteins, such as RIP1. Earlier studies have clearly highlighted the role of associated proteins in mediating A20's inhibitory function in NF-kB signalling in fibroblasts (Shembade et al, 2007, 2008; Iha et al, 2008). Together with the present work from the Harhaj laboratory (Shembade et al, 2009), these genetic and immunoprecipitation experiments suggest that negative regulation of NF-kB is mediated by a quaternary A20– TAX1BP1–Itch–RNF11 complex. "
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