MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway
- Sun Yat-sen University, China
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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.
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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
- Stephen P Goff, Howard Hughes Medical Institute, Columbia University, United States
Publication history
- Received: August 16, 2018
- Accepted: February 7, 2019
- Accepted Manuscript published: February 8, 2019 (version 1)
- 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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Further reading
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- Human Biology and Medicine
- Immunology and Inflammation
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- Immunology and Inflammation
- Microbiology and Infectious Disease
