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Downregulated NDR1 protein kinase inhibits innate immune response by initiating an miR146a-STAT1 feedback loop

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Listed:
  • Zhiyong Liu

    (Zhejiang University)

  • Qiang Qin

    (Zhejiang University)

  • Cheng Wu

    (Zhejiang University)

  • Hui Li

    (Zhejiang Cancer Hospital)

  • Jia’nan Shou

    (Zhejiang University)

  • Yuting Yang

    (Zhejiang University)

  • Meidi Gu

    (Zhejiang University)

  • Chunmei Ma

    (Zhejiang University)

  • Wenlong Lin

    (Zhejiang University)

  • Yan Zou

    (The Fourth Affiliated Hospital of Guangxi Medical University)

  • Yuanyuan Zhang

    (Zhejiang University)

  • Feng Ma

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Jihong Sun

    (Zhejiang University)

  • Xiaojian Wang

    (Zhejiang University)

Abstract

Interferon (IFN)-stimulated genes (ISGs) play crucial roles in the antiviral immune response; however, IFNs also induce negative regulators that attenuate the antiviral response. Here, we show that both viral and bacterial invasion downregulate Nuclear Dbf2-related kinase 1 (NDR1) expression via the type I IFN signaling pathway. NDR1 promotes the virus-induced production of type I IFN, proinflammatory cytokines and ISGs in a kinase-independent manner. NDR1 deficiency also renders mice more susceptible to viral and bacterial infections. Mechanistically, NDR1 enhances STAT1 translation by directly binding to the intergenic region of miR146a, thereby inhibiting miR146a expression and liberating STAT1 from miR146a-mediated translational inhibition. Furthermore, STAT1 binds to the miR146a promoter, thus decreasing its expression. Together, our results suggest that NDR1 promotion of STAT1 translation is an important event for IFN-dependent antiviral immune response, and suggest that NDR1 has an important role in controlling viral infections.

Suggested Citation

  • Zhiyong Liu & Qiang Qin & Cheng Wu & Hui Li & Jia’nan Shou & Yuting Yang & Meidi Gu & Chunmei Ma & Wenlong Lin & Yan Zou & Yuanyuan Zhang & Feng Ma & Jihong Sun & Xiaojian Wang, 2018. "Downregulated NDR1 protein kinase inhibits innate immune response by initiating an miR146a-STAT1 feedback loop," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05176-7
    DOI: 10.1038/s41467-018-05176-7
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