1. NLRX1 Negatively Regulates TLR-Induced NF-κB Signaling by Targeting TRAF6 and IKK
- Author
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Xia, Xiaojun, Cui, Jun, Wang, Helen Y., Zhu, Liang, Matsueda, Satoko, Wang, Qinfu, Yang, Xiaoang, Hong, Jun, Songyang, Zhou, Chen, Zhijian J., and Wang, Rong-Fu
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NF-kappa B , *GENETIC regulation , *IMMUNE response , *CELLULAR signal transduction , *GENE targeting , *NATURAL immunity , *PHOSPHORYLATION , *SEPTIC shock - Abstract
Summary: Tight regulation of NF-κB signaling is essential for innate and adaptive immune responses, yet the molecular mechanisms responsible for its negative regulation are not completely understood. Here, we report that NLRX1, a NOD-like receptor family member, negatively regulates Toll-like receptor-mediated NF-κB activation. NLRX1 interacts with TRAF6 or IκB kinase (IKK) in an activation signal-dependent fashion. Upon LPS stimulation, NLRX1 is rapidly ubiquitinated, disassociates from TRAF6, and then binds to the IKK complex, resulting in inhibition of IKKα and IKKβ phosphorylation and NF-κB activation. Knockdown of NLRX1 in various cell types markedly enhances IKK phosphorylation and the production of NF-κB-responsive cytokines after LPS stimulation. We further provide in vivo evidence that NLRX1 knockdown in mice markedly enhances susceptibility to LPS-induced septic shock and plasma IL-6 level. Our study identifies a previously unrecognized role for NLRX1 in the negative regulation of TLR-induced NF-κB activation by dynamically interacting with TRAF6 and the IKK complex. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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