TRIM30 alpha negatively regulates TLR-mediated NF-kappa B activation by targeting TAB2 and TAB3 for degradation

Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Nature Immunology (Impact Factor: 20). 05/2008; 9(4):369-77. DOI: 10.1038/ni1577
Source: PubMed


Toll-like receptor (TLR) signaling is pivotal to innate and adaptive immune responses and must be tightly controlled. The mechanisms of TLR signaling have been the focus of extensive studies. Here we report that the tripartite-motif protein TRIM30alpha, a RING protein, was induced by TLR agonists and interacted with the TAB2-TAB3-TAK1 adaptor-kinase complex involved in the activation of transcription factor NF-kappaB. TRIM30alpha promoted the degradation of TAB2 and TAB3 and inhibited NF-kappaB activation induced by TLR signaling. In vivo studies showed that transfected or transgenic mice overexpressing TRIM30alpha were more resistant to endotoxic shock. Consistent with that, in vivo 'knockdown' of TRIM30alpha mRNA by small interfering RNA impaired lipopolysaccharide-induced tolerance. Finally, expression of TRIM30alpha depended on NF-kappaB activation. Our results collectively indicate that TRIM30alpha negatively regulates TLR-mediated NF-kappaB activation by targeting degradation of TAB2 and TAB3 by a 'feedback' mechanism.

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    • "One subset of Trim proteins that include Trim5, Trim14, Trim15, and Trim44 has been shown to positively regulate the antiviral response by ubiquitinating multiple targets in the pathway (Ottosson et al., 2006; Reymond et al., 2001; Uchil et al., 2013; Yang et al., 2013). On the other hand, Trim21, Trim27, Trim30 and Trim38 were recently shown to function as negative regulators of the antiviral response by mediating proteasomal degradation of various signaling factors (Higgs et al., 2008; Shi et al., 2008; Zhao et al., 2012; Zurek et al., 2012). Interestingly, some Trims like Trim21 are functionally flexible and can regulate the innate immune pathway in a positive or negative manner. "
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    ABSTRACT: In this study, using an immunoprecipitation coupled with mass spectrometry approach, we have identified the E3 ubiquitin ligase Trim21 as an interacting partner of IFI35 and Nmi. We found that this interaction leads to K63-linked ubiquitination on K22 residue of Nmi, but not IFI35. Using domain deletion analysis, we found that the interaction is mediated via the coiled-coil domain of Nmi and the carboxyl-terminal SPRY domain of Trim21. Furthermore, we show that depletion of Trim21 leads to significantly reduced interaction of Nmi with IFI35, which results in the abrogation of the negative regulatory function of the Nmi-IFI35 complex on innate antiviral signaling. Thus, Trim21 appears to be a critical regulator of the functions of the Nmi-IFI35 complex. Overall, the results presented here uncover a new mechanism of regulation of the Nmi-IFI35 complex by Trim21, which may have implications for various autoimmune diseases associated uncontrolled antiviral signaling. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "In addition to proteasome recruitment, TRIM5a has been shown to generate unanchored Lys63-linked polyubiquitin (polyUb) chains upon binding to susceptible retroviral capsids. These unanchored polyUb chains are postulated to activate transforming growth factor-b-activated kinase 1 (TAK1), which in turn stimulates NF-jB nuclear translocation and induces antiviral gene expression (Shi et al, 2008; Pertel et al, 2011). The Ub enzymology underlying different TRIM5a activities remains to be defined. "
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    • "There is increasing evidence that TRIM proteins can activate or inhibit signal pathways downstream of PRRs and TLRs (Toll-like receptors) to modulate NF-jB activation [3]. Mouse TRIM30a negatively regulates TLR-mediated NF-jB activation by targeting TAB2 and TAB3 for degradation, resulting in the abrogation of TAK1 activation [8]. Protein kinases IKKb and IKKc are crucial regulators in the NF-jB signal pathway. "
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    ABSTRACT: The tripartite motif (TRIM)-containing proteins exhibit various activities and play important roles in the immune system through regulating signaling pathways. Bloodthirty gene is a multigene subset of TRIM genes. In this study we identified and characterized a new member of the bloodthirty subset of TRIM genes, btr20, in zebrafish (Danio rerio). The gene is located on chromosome 19 and forms a cluster with btr18, btr21, btr22 and an E3 ubiquitin ligase TRIM39-like gene. Deduced btr20 represents a RBCC-B30.2 TRIM protein containing 544 amino acids. The mRNA expression level of btr20 was highest in intestine and gill, followed by in spleen and kidney. Challenge experiment with Aeromonas hydrophila strain NJ-1 showed that the levels of btr20 and NF-κB mRNA were remarkably upregulated in the four tissues mentioned above. btr20 was localized in the cytoplasm and formed aggregate in human embryonic kidney cell line 293T. In vitro self-uniquitylation experiment demonstrated that btr20 has E3 ubiquitin ligase activity that can be self-ubiquitylated with most E2 enzymes, especially UbcH6. The results suggested that btr20 may involve in the anti-microbial activity in the immune system as an E3 ubiquitin ligase. Copyright © 2014. Published by Elsevier Inc.
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