The zinc finger protein A20 is encoded by an immediate early response gene whose expression is induced by different inflammatory stimuli, including interleukin-1 (IL-1). Gene induction by IL-1 is mediated by activation of the transcription factor NF-kappaB, and requires the signal adapter protein TRAF6. The latter interacts with the NF-kappaB-inducing kinase NIK, which is believed to be part of the IkappaB kinase complex. Expression of A20 potently inhibits IL-1-induced NF-kappaB activation by an unknown mechanism. Inhibition of IL-1-induced NF-kappaB activation was found to be mediated by the C-terminal zinc finger-containing domain of A20. More importantly, we present evidence that A20 interferes with IL-1-induced NF-kappaB activation at the level of TRAF6, upstream of NIK. Moreover, A20 was shown to directly interact with TRAF6.
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"For example, the RIG-I protein is down regulated by the host protein RFN125, CYLD, NLRC5, Casein kinase II and other kinases , , , , , ; the MAVS protein is also negatively regulated by the host proteins NLRX1 and PCBP2 , , and is cleaved from the mitochondria surface by the NS3/4 protease of the hepatitis C virus (HCV) . Moreover, the adaptor proteins TRAF3 and TRAF6 are targeted by the cellular proteins DUBA and A20 , , and TBK1 is sequestered by SIKE . The transcription activator IRF3 is under negative regulation by host protein Pin1 and MafB, and HIV accessory proteins VPR and Vif , , , and the p65 subunit of NFκB is targeted for degradation by PDLIM2 . "
[Show abstract][Hide abstract] ABSTRACT: The production of type I interferons (IFNs) in response to viral infections is critical for antiviral immunity. However, IFN production is transient, and continued expression can lead to inflammatory or autoimmune diseases. Thus, understanding the mechanisms underlying the negative regulation of IFN expression could lead to the development of novel therapeutic approaches to the treatment of these diseases. We report that the transcription factor IRF3 plays a central role in the negative regulation of interferon-β (IFNβ) expression during both acute and persistent (chronic) virus infections. We show that the degradation of IRF3 during acute infections, rather than the activation of transcriptional repressors, leads to the down regulation of IFNβ expression. We also show that the block to IFNβ expression in mouse embryonic fibroblasts that are persistently infected with Sendai virus (SeV) correlates with the absence of transcriptionally active IRF3. Remarkably, ongoing protein synthesis and viral replication are required to maintain repression of the IFNβ gene in persistently infected cells, as the gene can be activated by the protein synthesis inhibitor cycloheximide, or by the antiviral drug ribavirin. Finally, we show that the SeV V protein inhibits IRF3 activity in persistently infected cells. Thus, in conjunction with the known interference with STAT1 by the SeV C protein, both IFN activation and its signaling pathways are blocked in persistently infected cells. We conclude that the transcription factor IRF3 is targeted for turnover and inactivation through distinct mechanisms from both the host cells and virus, leading to the inhibition of IFNβ gene expression during acute and persistent viral infections. These observations show that IRF3 plays a critical role, not only in the activation of the IFNβ gene, but also in the controlling the duration of its expression. (284 words).
"The signaling abilities of several members of the NGF/TNF receptor family can be modulated by the interaction of their effectors with other cellular proteins. I-TRAF and A20 can interact with several TRAF proteins and repress NF-kB induction in response to TNF-a or IL-1 (Rothe et al. 1996) (Song et al. 1996) (Heyninck and Beyaert 1999). "
[Show abstract][Hide abstract] ABSTRACT: Nerve growth factor (NGF) regulates the activity of the transcription factor NF-κB (nuclear factor-κB) through its low affinity receptor, p75. In the present study we found that NGF binding to p75 induces nuclear translocation of p65 and increases NF-κB binding activity in a cell line overexpressing p75, but only after the cells have been subjected to a previous stress. Under physiological conditions, in the absence of stress, NGF is unable to alter p65 nuclear levels. Tumor necrosis factor-α (TNF-α) induces a down-regulation of IκB-α, -β and -ε both in physiological and in stress, i.e. serum-free, conditions. In contrast, NGF only induces the specific degradation of IκB-β after serum withdrawal, without affecting IκB-α or -ε either in the presence or in the absence of stress. IκB-β consists of several isoforms, whose relative abundance is regulated by serum withdrawal. NGF does not target all the IκB-β isoforms with the same potency, being more effective in reducing the levels of the isoforms up-regulated by serum withdrawal. TRAF-6 is expressed at the same level under both physiological and stress conditions. These results indicate that NGF is able to induce NF-κB nuclear translocation by a mechanism that involves specific IκB-β degradation only after the cells have been subjected to a severe stress.
Preview · Article · Jul 2008 · Journal of Neurochemistry
"One reason for the more tissue-restricted phenotype of TAX1BP1-deficient mice might be the redundancy with other A20 adaptor proteins. In this context, A20 has been shown to bind three different ABIN family members, which have been suggested to be involved in the NF-kB inhibitory function of A20 (Heyninck and Beyaert, 1999; Van Huffel et al, 2001; Wullaert et al, 2007). Moreover, ABIN-1 was recently shown to facilitate the binding of A20 to NEMO and to be essential for NEMO de-ubiquitination by A20 (Mauro et al, 2006). "
[Show abstract][Hide abstract] ABSTRACT: Nuclear factor kappa B (NF-kappaB) is a key mediator of inflammation. Unchecked NF-kappaB signalling can engender autoimmune pathologies and cancers. Here, we show that Tax1-binding protein 1 (TAX1BP1) is a negative regulator of TNF-alpha- and IL-1beta-induced NF-kappaB activation and that binding to mono- and polyubiquitin by a ubiquitin-binding Zn finger domain in TAX1BP1 is needed for TRAF6 association and NF-kappaB inhibition. Mice genetically knocked out for TAX1BP1 are born normal, but develop age-dependent inflammatory cardiac valvulitis, die prematurely, and are hypersensitive to low doses of TNF-alpha and IL-1beta. TAX1BP1-/- cells are more highly activated for NF-kappaB than control cells when stimulated with TNF-alpha or IL-1beta. Mechanistically, TAX1BP1 acts in NF-kappaB signalling as an essential adaptor between A20 and its targets.