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Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation

Nature Chemical Biology volume 11, pages 339346 (2015) | Download Citation

Abstract

Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.

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Acknowledgements

This work was supported by grants from the National Natural Science Fund of China, the '973' Project of the Ministry of Science and Technology (91413113, 2014CB910602, 31370724, 31221065) and the Program of Introducing Talents of Discipline to Universities (B12001). The crystallographic data collection at Beamline BL17U1 at Shanghai Synchrotron Radiation Facility is gratefully acknowledged.

Author information

Author notes

    • Li Li
    • , Yuan Liu
    • , Hang-zi Chen
    •  & Feng-wei Li

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.

    • Li Li
    • , Yuan Liu
    • , Hang-zi Chen
    • , Feng-wei Li
    • , Jian-feng Wu
    • , Jian-ping He
    • , Yong-zhen Xing
    • , Yan Chen
    • , Wei-jia Wang
    • , Xu-yang Tian
    • , An-zhong Li
    • , Qian Zhang
    • , Jiahuai Han
    • , Tianwei Lin
    •  & Qiao Wu
  2. Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, China.

    • Hong-kui Zhang
    •  & Pei-qiang Huang

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Contributions

The Wu laboratory (L.L., Y.L., H.C., J. He, Y.X., Y.C. and W.W.) was responsible for the experiments on molecular cellular biology and detection in mice. The Lin laboratory (F.L., X.T., A.L., Q.Z.) was responsible for the structure determination and analysis. The Han laboratory (J.W.) provided p38αfl/fl and LtrLysCre-p38αΔ/Δ mice. The Huang laboratory (H.Z.) provided the compounds. J. Han was involved in the discussion of the manuscript. Q.W. and T.L. designed the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Tianwei Lin or Qiao Wu.

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https://doi.org/10.1038/nchembio.1788

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