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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    ABSTRACT: Two distinct p97 membrane fusion pathways are required for Golgi biogenesis: the p97/p47 and p97/p37 pathways. VCIP135 is necessary for both pathways, while its deubiquitinating activity is required only for the p97/p47 pathway. We have now identified a novel VCIP135-binding protein, WAC. WAC localizes to the Golgi as well as the nucleus. In Golgi membranes, WAC is involved in a complex containing VCIP135 and p97. WAC directly binds to VCIP135 and increases its deubiquitinating activity. siRNA experiments revealed that WAC is required for Golgi biogenesis. In an in vitro Golgi reformation assay, WAC was necessary only for p97/p47-mediated Golgi reassembly, but not for p97/p37-mediated reassembly. WAC is hence thought to function in p97/p47-mediated Golgi membrane fusion by activating the deubiquitinating function of VCIP135. We also showed that the two p97 pathways function in ER membrane fusion as well. An in vitro ER reformation assay revealed that both pathways required VCIP135 but not its deubiquitinating activity for their ER membrane fusion. This was consistent with the finding that WAC is unnecessary for p97-mediated ER membrane fusion.
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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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    ABSTRACT: Our previous study showed Human T-cell leukemia virus type 1 Tax induces osteopontin (OPN) expression by transactivating its promoter. As an extension, we investigated here the possible influence of Tax on CD44, an important receptor for OPN. Co-expression of Tax, but not its NF-κB-defective mutant, significantly increased the reporter gene expression directed by CD44 promoter. Tax-mediated CD44 activation was largely diminished by disrupting an element similar to the noncanonical κβ site found in other IKKα target genes, and further, co-transfection of RelB siRNA abolished CD44 induction by Tax, suggesting an involvement of noncanonical NF-κB pathway in Tax-mediated transactivation. Consistently, chromatin immunoprecipitation revealed a specific interaction of CD44 promoter with RelB-containing complex. Together, these results indicate that D44 gene is one of the downstream target genes of aberrantly activated noncanonical NF-κB signaling by Tax, providing an additional line of evidence explaining how Tax-induced NF-κB signaling is integrated into a fate-determining cellular program.
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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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