Interferon‐mediated repression of miR‐324‐5p potentiates necroptosis to facilitate antiviral defense. (23rd June 2022)

• Record Type: Journal Article
• Authors: Dou, Xiaoyan; Yu, Xiaoliang; Du, Shujing; Han, Yu; Li, Liang; Zhang, Haoran; Yao, Ying; Du, Yayun; Wang, Xinhui; Li, Jingjing; Yang, Tao; Zhang, Wei; Yang, Chengkui; Ma, Feng; He, Sudan
• Is Part Of: EMBO reports. Volume 23:Number 8(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-06-23
• Subjects: antiviral defense -- interferon -- miR‐324‐5p -- MLKL -- necroptosis; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202154438
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: 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. Synopsis: Expression of MLKL, the terminal effector of necroptosis, is reduced by miR‐324‐5p. Interferon signaling decreases miR‐324‐5p levels via the JAK/STAT1 pathway, thereby stabilizing MLKL and potentiating necroptosis in influenza virus‐infected cells to limit viral replication. MiR‐324‐5p downregulates MLKL and thus inhibits necroptosis. MiR‐324‐5p targets MLKL in a seed region‐independent and species‐specific manner. IFN‐induced JAK‐STAT1‐mediated downregulation of miR‐324‐5p post‐transcriptionally promotes MLKL expression. The IFN‐miR‐324‐5p‐MLKL axis protects host cells against influenza A virus infection. Abstract : Expression of MLKL, the terminal effector of necroptosis, is reduced by miR‐324‐5p. Interferon signaling decreases miR‐324‐5p levels via the JAK/STAT1 pathway, thereby stabilizing MLKL and potentiating necroptosis in influenza virus‐infected cells to limit viral replication.