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: 10.43). 10/2007; 26(17):3910-22. DOI: 10.1038/sj.emboj.7601823
Source: PubMed


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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    • "One of the genes revealed by this study, TAX1BP1, produces human T-cell leukemia virus type I binding protein 1, which interacts with other important molecules such as A20 and TRAF6, which participate in inflammatory response processes (22). The CD163 gene encodes a multiligand scavenger receptor protein exclusively expressed by monocytes and macrophages. "
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    ABSTRACT: Nasal polyps (NP) is highly associated with the disorder of immune cells. Alternative polyadenylation (APA) produces mRNA isoforms with different length of 3'‑untranslated region (UTR) and regulates gene expression. It has been proven that this APA-mediated regulation of 3'UTR length is an immune-associated phenomenon. The aim of this study was to investigate the genome-wide alternative tandem 3'UTR length switching events in non-eosinophilic nasal polyp tissue. Thirteen patients diagnosed as having non-eosinophilic nasal polyps were included in this study. Nasal polyp tissue and control mucosa were collected during surgery. The 3' end library of cDNA was constructed. The recovered libraries were sequenced with second sequencing technology, and the sequencing data were analyzed by an in-house bioinformatics pipeline. Tandem 3'UTR length switching between samples was detected by a test of linear trend alternative to independence. We found a significant alteration in the tandem 3'UTR length in 1,920 genes in nasal polyp samples. Functional annotation results showed that several gene ontology (GO) terms were enriched in the list of genes with switched APA sites, including regulation of transcription, macromolecule catabolic localization and mRNA processing.The results suggested that APA-mediated alternative 3'UTR regulation plays an important role in the post-transcriptional regulation of gene expression in non-eosinophilic nasal polyps.
    International Journal of Molecular Medicine 04/2014; 33(6). DOI:10.3892/ijmm.2014.1734 · 2.09 Impact Factor
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    • "A20 cleaves Lys63 (K63)-linked polyubiquitin chains on overlapping substrates, such as E3 ubiquitin ligase TRAF6 and adaptor molecule RIP1, with the help of the substrate-specific adaptor Tax1-binding protein 1 (Tax1bp1 [7], [8]). Tax1bp1 intrinsically regulates NF-κB by recruiting A20 to the target molecules to remove their polyubiquitin chains, which play important roles in their assembly into the IKK complex [8], [9]. Deficiencies in A20 or Tax1bp1 lead to uncontrolled and spontaneous systemic inflammation in mice as a result of unchecked NF-κB signaling [8], [10]. "
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    ABSTRACT: Tax1-binding protein 1 (Tax1bp1) negatively regulates NF-κB by editing the ubiquitylation of target molecules by its catalytic partner A20. Genetically engineered TAX1BP1-deficient (KO) mice develop age-dependent inflammatory constitutions in multiple organs manifested as valvulitis or dermatitis and succumb to premature death. Laser capture dissection and gene expression microarray analysis on the mitral valves of TAX1BP1-KO mice (8 and 16 week old) revealed 588 gene transcription alterations from the wild type. SAA3 (serum amyloid A3), CHI3L1, HP, IL1B and SPP1/OPN were induced 1,180-, 361-, 187-, 122- and 101-fold respectively. WIF1 (Wnt inhibitory factor 1) exhibited 11-fold reduction. Intense Saa3 staining and significant I-κBα reduction were reconfirmed and massive infiltration of inflammatory lymphocytes and edema formation were seen in the area. Antibiotics-induced 'germ free' status or the additional MyD88 deficiency significantly ameliorated TAX1BP1-KO mice's inflammatory lesions. These pathological conditions, as we named 'pseudo-infective endocarditis' were boosted by the commensal microbiota who are usually harmless by their nature. This experimental outcome raises a novel mechanistic linkage between endothelial inflammation caused by the ubiquitin remodeling immune regulators and fatal cardiac dysfunction.
    PLoS ONE 09/2013; 8(9):e73205. DOI:10.1371/journal.pone.0073205 · 3.23 Impact Factor
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    • "A20 is a protein induced during TLR stimulation that has two enzymatic activities where it can act as both an E3 ubiquitin ligase and a deubiquitinase. In vitro analyses have shown that A20 restricts NF-κB activation by modulating RIP1 and TRAF6 [30]. Shi et al. (2007) identified TRIM30α as, whose expression was upregulated by various TLR agonists, including LPS, as a negative regulator of TLR4 signaling [31]. "
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    ABSTRACT: Toll-like receptors (TLRs) play a pivotal role in the defense against invading pathogens by detecting pathogen-associated molecular patterns (PAMPs). TLR4 recognizes lipopolysaccharides (LPS) in the cell walls of Gram-negative bacteria, resulting in the induction and secretion of proinflammatory cytokines such as TNF-α and IL-6. The WW domain containing E3 ubiquitin protein ligase 1 (WWP1) regulates a variety of cellular biological processes. Here, we investigated whether WWP1 acts as an E3 ubiquitin ligase in TLR-mediated inflammation. Knocking down WWP1 enhanced the TNF-α and IL-6 production induced by LPS, and over-expression of WWP1 inhibited the TNF-α and IL-6 production induced by LPS, but not by TNF-α. WWP1 also inhibited the IκB-α, NF-κB, and MAPK activation stimulated by LPS. Additionally, WWP1 could degrade TRAF6, but not IRAK1, in the proteasome pathway, and knocking down WWP1 reduced the LPS-induced K48-linked, but not K63-linked, polyubiquitination of endogenous TRAF6. We identified WWP1 as an important negative regulator of TLR4-mediated TNF-α and IL-6 production. We also showed that WWP1 functions as an E3 ligase when cells are stimulated with LPS by binding to TRAF6 and promoting K48-linked polyubiquitination. This results in the proteasomal degradation of TRAF6.
    PLoS ONE 06/2013; 8(6):e67633. DOI:10.1371/journal.pone.0067633 · 3.23 Impact Factor
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