Article

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

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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    • "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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    • "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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