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: 24.97). 05/2008; 9(4):369-77. DOI: 10.1038/ni1577
Source: PubMed

ABSTRACT 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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Available from: Mude Shi, Jul 27, 2015
    • "Our screen reveals a broad engagement of TRIMs in autophagy . Additional work supports TRIM connections with autophagy: TRIM13 overexpression can induce autophagy (Tomar et al., 2012); TRIM28 may regulate autophagy (Barde et al., 2013; Yang et al., 2013); several TRIMs interact with p62 (Fusco et al., 2012; Khan et al., 2014; Kim and Ozato, 2009; Pizon et al., 2013; Tomar et al., 2012); the expression of TRIM55 correlates with that of autophagy factors (Perera et al., 2011; Pizon et al., 2013); TRIMs are on lists in genome-wide autophagy screens (Behrends et al., 2010; Lipinski et al., 2010; McKnight et al., 2012); and TRIM21 and murine TRIM30a induce lysosomal degradation of certain targets (Niida et al., 2010; Shi et al., 2008). "
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    ABSTRACT: Autophagy, a homeostatic process whereby eukaryotic cells target cytoplasmic cargo for degradation, plays a broad role in health and disease states. Here we screened the TRIM family for roles in autophagy and found that half of TRIMs modulated autophagy. In mechanistic studies, we show that TRIMs associate with autophagy factors and act as platforms assembling ULK1 and Beclin 1 in their activated states. Furthermore, TRIM5α acts as a selective autophagy receptor. Based on direct sequence-specific recognition, TRIM5α delivered its cognate cytosolic target, a viral capsid protein, for autophagic degradation. Thus, our study establishes that TRIMs can function both as regulators of autophagy and as autophagic cargo receptors, and reveals a basis for selective autophagy in mammalian cells.
    Developmental Cell 08/2014; 30(4). DOI:10.1016/j.devcel.2014.06.013 · 10.37 Impact Factor
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    • "TRIM5 is capable of activating mitogen activated protein kinases (MAPK)-and NF-␬B-dependent inflammatory genes involved in the innate immune response similar to those activated by the gram-negative bacterial cell wall component lipopolysaccharide (LPS) (Pertel et al., 2011) through Toll-like receptor 4 (Brenchley et al., 2006). Further investigation revealed that TRIM5 interacts with transforming growth factor beta-activated kinase 1 (TAK1), TAK1-binding protein 2 (TAB2), and TAB3, components of the TAK1 kinase complex, in order to activate MAPK and NF-␬B signaling pathways (Shi et al., 2008). "
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    ABSTRACT: JMJD3, a Jumonji C family histone demethylase, plays an important role in the regulation of inflammation induced by the transcription factor nuclear factor-kappa B (NF-κB) in response to various stimuli. JMJD3 is a histone-3 lysine-27 trimethylation (H3K27me3) demethylase, a histone mark associated with transcriptional repression and activation of a diverse set of genes. The present study assessed stable JMJD3 knockdown (KD)-dependent proteomic profiling in human leukemia monocyte (THP-1) cells to analyze the JMJD3-mediated differential changes of marker expression in inflammatory cells. To analyze the protein expression profile of tumor necrosis factor-alpha (TNF-α)-stimulated JMJD3-kd THP-1 cells, we employed matrix-assisted-laser-desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Additionally, Ingenuity Pathways Analysis (IPA) was applied to establish the molecular networks. A comparative proteomic profile was determined in TNF-α-treated both of JMJD3-kd THP-1 cells and THP-1 scrambled (sc) cells. The expression of tripartite motif protein (TRIM5), glutathione peroxidase (GPx), glia maturation factor-γ (GMFG), caspase recruitment domain family, member 14 (CARMA2), and dUTP pyrophosphatase were significantly down-regulated, whereas heat shock protein beta-1 (HspB1) and prohibition were significantly up-regulated in JMJD3-kd THP-1 cells. The molecular and signaling networks of the differentially expressed proteins in JMJD3-kd THP-1 cells were determined by IPA. The molecular network signatures and functional proteomics obtained in this study may facilitate the suppression of different key inflammatory regulators through JMJD3-attenuation, which would be crucial to evaluate potential therapeutic targets and to elucidate the molecular mechanism of JMJD3-kd dependent effects in THP-1 cells.
    Molecular Immunology 05/2013; 56(1-2):113-122. DOI:10.1016/j.molimm.2013.04.013 · 3.00 Impact Factor
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    • "Compared to TRIM79α mRNA levels in the skin, TRIM79α mRNA was enriched in organs involved in immune regulation, including spleen, lymph node and bone marrow, and was detectable in lung and liver (Figure 1B). This is reminiscent of the tissue distribution of TRIM30α, the murine TRIM closest to TRIM79α (Shi et al., 2008). "
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    ABSTRACT: In response to virus infection, type I interferons (IFNs) induce several genes, most of whose functions are largely unknown. Here, we show that the tripartite motif (TRIM) protein, TRIM79α, is an IFN-stimulated gene (ISG) product that specifically targets tick-borne encephalitis virus (TBEV), a Flavivirus that causes encephalitides in humans. TRIM79α restricts TBEV replication by mediating lysosome-dependent degradation of the flavivirus NS5 protein, an RNA-dependent RNA polymerase essential for virus replication. NS5 degradation was specific to tick-borne flaviviruses, as TRIM79α did not recognize NS5 from West Nile virus (WNV) or inhibit WNV replication. In the absence of TRIM79α, IFN-β was less effective in inhibiting tick-borne flavivirus infection of mouse macrophages, highlighting the importance of a single virus-specific ISG in establishing an antiviral state. The specificity of TRIM79α for TBEV reveals a remarkable ability of the innate IFN response to discriminate between closely related flaviviruses.
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