MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway

Abstract

MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and a central player in liver biology and disease. Herein, we report a previously unknown role for miR-122 in hepatocyte intrinsic innate immunity. Restoring miR-122 levels in hepatoma cells markedly enhanced the activation of interferons (IFNs) in response to a variety of viral nucleic acids or simulations, especially of hepatitis C virus RNA and poly (I:C). Mechanistically, miR-122 down-regulated the phosphorylation (Tyr705) of STAT3 and thereby removed the negative regulation of STAT3 on IFN-signaling. While STAT3 represses IFN expression by inhibiting interferon regulatory factor 1 (IRF1), miR-122 targets MERTK, FGFR1 and IGF1R, three receptor tyrosine kinases (RTKs) that directly promote STAT3 phosphorylation. This work identifies a miR-122-RTKs/STAT3-IRF1-IFNs regulatory circuitry, which may play a pivotal role in regulating hepatocyte innate immunity. These findings renewed our knowledge about miR-122's function and have important implications for treating hepatitis viruses.

Data availability

Microarray data have been deposited in GEO under accession number GSE99663.

The following data sets were generated

Article and author information

Author details

  1. Hui Xu

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Shi-Jun Xu

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Shu-Juan Xie

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yin Zhang

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Jian-Hua Yang

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3863-2786
  6. Wei-Qi Zhang

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Man-Ni Zheng

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Hui Zhou

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Liang-Hu Qu

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    For correspondence
    lssqlh@mail.sysu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3657-2863

Funding

National Natural Science Foundation of China (31200593)

  • Hui Xu

National Natural Science Foundation of China (31230042)

  • Liang-Hu Qu

National Natural Science Foundation of China (31471223)

  • Liang-Hu Qu

National Natural Science Foundation of China (31671349)

  • Liang-Hu Qu

Natural Science Foundation of Guangdong Province (2014A030313163)

  • Hui Xu

National Basic Research Program of China (2011CB811300)

  • Liang-Hu Qu

National Key R&D Program of China (2017YFA0504400)

  • Jian-Hua Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Stephen P Goff, Howard Hughes Medical Institute, Columbia University, United States

Version history

  1. Received: August 16, 2018
  2. Accepted: February 7, 2019
  3. Accepted Manuscript published: February 8, 2019 (version 1)
  4. Version of Record published: February 25, 2019 (version 2)

Copyright

© 2019, Xu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hui Xu
  2. Shi-Jun Xu
  3. Shu-Juan Xie
  4. Yin Zhang
  5. Jian-Hua Yang
  6. Wei-Qi Zhang
  7. Man-Ni Zheng
  8. Hui Zhou
  9. Liang-Hu Qu
(2019)
MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway
eLife 8:e41159.
https://doi.org/10.7554/eLife.41159

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https://doi.org/10.7554/eLife.41159