Journal
EMBO REPORTS
Volume 23, Issue 8, Pages -Publisher
WILEY
DOI: 10.15252/embr.202154438
Keywords
antiviral defense; interferon; miR-324-5p; MLKL; necroptosis
Categories
Funding
- National Natural Science Foundation of China [31830051, 31671436, 31900526, 31771533, 3160010179]
- National Key Research and Development Program of China [2018YFA0900803]
- CAMS Innovation Fund for Medical Sciences [2021-I2M-1-041, 2021-I2M-1-047, 2021-I2M-1-061]
- Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2021-PT180-001, 2019PT310028, 2017NL31004, 2017NL31002]
- Priority Academic Program Development of Jiangsu Higher Education Institutions, China Postdoctoral Science Foundation-funded project [2019 M650563]
- Natural Science Foundation of Jiangsu Province Grant [BK20160314]
- Fok Ying Tung Education Foundation for Young Teachers [151020]
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MiR-324-5p negatively regulates necroptosis by targeting MLKL expression, and its downregulation by interferons facilitates the activation of necroptosis for host antiviral defense.
Mixed lineage kinase domain-like protein (MLKL) is the terminal effector of necroptosis, a form of regulated necrosis. Optimal activation of necroptosis, which eliminates infected cells, is critical for antiviral host defense. MicroRNAs (miRNAs) regulate the expression of genes involved in various biological and pathological processes. However, the roles of miRNAs in necroptosis-associated host defense remain largely unknown. We screened a library of miRNAs and identified miR-324-5p as the most effective suppressor of necroptosis. MiR-324-5p downregulates human MLKL expression by specifically targeting the 3 ' UTR in a seed region-independent manner. In response to interferons (IFNs), miR-324-5p is downregulated via the JAK/STAT signaling pathway, which removes the posttranscriptional suppression of MLKL mRNA and facilitates the activation of necroptosis. In influenza A virus (IAV)-infected human primary macrophages, IFNs are induced, leading to the downregulation of miR-324-5p. MiR-324-5p overexpression attenuates IAV-associated necroptosis and enhances viral replication, whereas deletion of miR-324-5p potentiates necroptosis and suppresses viral replication. Hence, miR-324-5p negatively regulates necroptosis by manipulating MLKL expression, and its downregulation by IFNs orchestrates optimal activation of necroptosis in host antiviral defense.
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