I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction

Tularik, Inc., South San Francisco, CA 94080, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/1996; 93(16):8241-6. DOI: 10.1073/pnas.93.16.8241
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Tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins associate with and transduce signals from TNF receptor 2, CD40, and presumably other members of the TNF receptor superfamily. TRAF2 is required for CD40- and TNF-mediated activation of the transcription factor NF-kappa B. Here we describe the isolation and characterization of a novel TRAF-interacting protein, I-TRAF, that binds to the conserved TRAF-C domain of the three known TRAFs. Overexpression of I-TRAF inhibits TRAF2-mediated NF-kappa B activation signaled by CD40 and both TNF receptors. Thus, I-TRAF appears as a natural regulator of TRAF function that may act by maintaining TRAFs in a latent state.

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    • "TANK (also known as I-TRAF) was first identified by two groups working independently to find binding partners of TNF-receptor associated factor (TRAF) family proteins. Cheng and Baltimore showed that TANK was a net activator of TRAF2- mediated NF-kappa B activation whereas Rothe et al. found that TANK inhibited TRAF2- dependent signaling (Cheng and Baltimore, 1996; Rothe et al., 1996). TANK has also been found to be a potent suppressor of Toll-like receptor (TLR)-mediated induction of proinflammatory cytokines (Kawagoe et al., 2009). "
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    ABSTRACT: Peripheral nerve injury evokes rapid and complex changes in gene transcription and cellular signaling pathways. Understanding how these changes are functionally related is essential for developing new approaches that accelerate and improve nerve regeneration. Towards this goal we found that nerve injury induces a rapid and significant up-regulation of the transcription factor Sox11 in dorsal root ganglia (DRG) neurons. Gain and loss of function studies have shown this increase is essential for normal axon regeneration. To determine how Sox11 impacts neuronal gene expression, DRG neurons were treated with Sox11 siRNA to identify potential transcriptional targets. One gene significantly reduced by Sox11 knockdown was TRAF (tumor necrosis factor (TNF) receptor-associated factor)-associated NF-κB activator (TANK). Here we show that TANK is expressed in DRG neurons, that TANK expression is increased in response to peripheral nerve injury and that Sox11 overexpression in vitro increases TANK expression. Injury and in vitro overexpression were also found to preferentially increase TANK transcript variant 3 and a larger TANK protein isoform. To determine if Sox11 regulates TANK transcription bioinformatic analysis was used to identify potential Sox binding motifs within 5 kbp of the TANK 5' untranslated region (UTR) across several mammalian genomes. Two sites in the mouse TANK gene were examined. Luciferase expression assays coupled with site-directed mutagenesis showed each site contributes to enhanced TANK promoter activity. In addition, chromatin immunoprecipitation assays showed direct Sox11 binding in regions containing the two identified Sox motifs in the mouse TANK 5'-UTR. These studies are the first to show that TANK is expressed in DRG neurons, that TANK is increased by peripheral nerve injury and that the regulation of TANK expression is, at least in part, controlled by the injury-associated transcription factor Sox11.
    Neuroscience 11/2012; 231. DOI:10.1016/j.neuroscience.2012.11.034 · 3.36 Impact Factor
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    • "Xenopus Tlrs5 protein is a paralog of TLR5 because a Xenopus ortholog of TLR5 has been registered in the NCBI database (NCBI Accession Number: NP_001088449), and both tlrs5 and tlr5 genes have been distinctly identified in fish (Tsujita et al. 2004; Baoprasertkul et al. 2007). In mammals, TANK (also called I- TRAF) protein has been identified as an adaptor molecule for TRAF-mediated NF-jB activation (Cheng & Baltimore 1996; Rothe et al. 1996). The Xenopus Tank showed 29% identity and 45% similarity to human TANK at amino acid sequence level (Fig. S3B in Supporting Information). "
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    ABSTRACT: FADD is an adaptor protein that transmits apoptotic signals from death receptors. Additionally, FADD has been shown to play a role in various functions including cell proliferation. However, the physiological role of FADD during embryonic development remains to be delineated. Here, we show the novel roles FADD plays in development and the molecular mechanisms of these roles in Xenopus embryos. By whole-mount in situ hybridization and RT-PCR analysis, we observed that fadd is constantly expressed in early embryos. The upregulation or downregulation of FADD proteins by embryonic manipulation resulted in induction of apoptosis or size changes in the heart during development. Expression of a truncated form of FADD, FADDdd, which lacks pro-apoptotic activity, caused growth retardation of embryos associated with dramatic expressional fluctuations of genes that are regulated by NF-κB. Moreover, we isolated a homolog of mammalian cullin-4 (Cul4), a component of the ubiquitin E3 ligase family, as a FADDdd-interacting molecule in Xenopus embryos. Thus, our study shows that FADD has multiple functions in embryos; it plays a part in the regulation of NF-κB activation and heart formation, in addition to apoptosis. Furthermore, our findings provide new insights into how Cul4-based ligase is related to FADD signaling in embryogenesis.
    Genes to Cells 10/2012; 17(11):875-96. DOI:10.1111/gtc.12004 · 2.81 Impact Factor
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    • "ISKNV causes a serious disease with high mortality rates in mandarin fish (Siniperca chuatsi), which severely damages the mandarin fish populations in China. Iridoviruses are icosahedral cytoplasmic DNA viruses that infect invertebrates and poikilothermic vertebrates, including insects, fish, amphibians, and reptiles [10]. Based on the Eighth Report of the International Committee on Taxonomy of Viruses (ICTV), the Iridoviridae family is subdivided into five genera, namely, Iridovirus, Chloriridovirus, Ranavirus, Lymphocystisvirus, and Megalocytivirus. "
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    ABSTRACT: Infectious spleen and kidney necrosis virus (ISKNV) is the type species of the Megalocytivirus genus of the Iridoviridae family. It causes a serious and potentially pandemic disease in wild and cultured fishes. ISKNV infection induces evident apoptosis in mandarin fish (Siniperca chuatsi) and zebrafish (Danio renio). However, the mechanism is still unknown. After a genome-wide bioinformatics analysis of ISKNV-encoded proteins, the ISKNV open reading frame 111L (ORF111L) shows a high similarity to the tumour necrosis factor receptor-associated factor (TRAF) encoded by fish, mice and mammals, which is essential for apoptotic signal transduction. Moreover, ORF111L was verified to directly interact with the zebrafish TNF receptor type 1 associated death domain protein (TRADD). A recombinant plasmid containing the DNA sequence of ORF111L was constructed and microinjected into zebrafish embryos at the 1-2 cell stage to investigate its biological function in vivo. ORF111L overexpression in the embryos resulted in increased apoptosis. ORF111L-induced apoptosis was clearly associated with significant caspase 8 upregulation and activation. The knockdown of zebrafish caspase 8 expression effectively blocked the apoptosis induced by ORF111L overexpression. Significantly, ORF111L overexpression resulted in much stronger effect on caspase 8 and caspase 3 upregulation compared to zebrafish TRAF2. This is the first report of a viral protein similar to TRAF that interacts with TRADD and induces caspase 8-mediated apoptosis, which may provide novel insights into the pathogenesis of ISKNV infection.
    PLoS ONE 05/2012; 7(5):e37001. DOI:10.1371/journal.pone.0037001 · 3.23 Impact Factor
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