NLRX1 Negatively Regulates TLR-Induced NF-κB Signaling by Targeting TRAF6 and IKK

Xiaojun Xia, Jun Cui, Helen Y. Wang, Liang Zhu, Satoko Matsueda, Qinfu Wang, Xiaoang Yang, Jun Hong, Zhou Songyang, Zhijian J. Chen, Rong Fu Wang

Research output: Contribution to journalArticle

168 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)843-853
Number of pages11
JournalImmunity
Volume34
Issue number6
DOIs
StatePublished - Jun 24 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Xia, X., Cui, J., Wang, H. Y., Zhu, L., Matsueda, S., Wang, Q., Yang, X., Hong, J., Songyang, Z., Chen, Z. J., & Wang, R. F. (2011). NLRX1 Negatively Regulates TLR-Induced NF-κB Signaling by Targeting TRAF6 and IKK. Immunity, 34(6), 843-853. https://doi.org/10.1016/j.immuni.2011.02.022