Hepatitis A virus-induced hsa-miR-146a-5p attenuates IFN-β signaling by targeting adaptor protein TRAF6

• Published in: Archives of virology 2021-03, Vol.166 (3), p.789-799
• Main Authors: Mo, Ling, Zeng, Zhaoping, Deng, Rongzhen, Li, Zhiyuan, Sun, Jing, Hu, Ningzhu, Shi, Jiandong, Hu, Yunzhang
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Cell Line; Gene Expression Regulation; Hepatitis A; Hepatitis A - pathology; Hepatitis A Virus, Human - genetics; Hepatitis A Virus, Human - growth & development; Humans; Immune response; Infectious Diseases; Innate immunity; Interferon; Interferon-gamma - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Medical Microbiology; MicroRNAs; MicroRNAs - genetics; miRNA; Non-coding RNA; Original Article; Proteins; Signal transduction; Signal Transduction - genetics; Signal Transduction - immunology; TRAF6 protein; Tumor necrosis factor; Tumor necrosis factor receptors; Virology; Virus Replication; Western blotting; β-Interferon
• ISSN: 0304-8608; 1432-8798
• DOI: 10.1007/s00705-021-04952-z

Hepatitis A virus (HAV), a unique hepatotropic human picornavirus, is the causative agent of acute hepatitis A in humans. Some studies have shown that HAV antagonizes the innate immune response by disrupting interferon-beta (IFN-β) signaling by viral proteins. However, whether microRNAs (miRNAs), a class of non-coding RNAs, are involved in the antagonism of IFN-β induction upon HAV infection is still unclear. In this study, we investigated the effects and mechanisms by which HAV-induced miRNAs antagonize IFN-β signaling. A variety of analytical methods, including miRNA microarray, RT-qPCR, dual-luciferase reporter assay, and Western blotting, were performed using HAV-infected cells. The results indicated that HAV infection upregulates the expression of hsa-miR-146a-5p, which in turn partially suppresses the induction of IFN-β synthesis, thereby promoting viral replication. Mechanistically, TRAF6 (TNF receptor-associated factor 6), a key adaptor protein in the RIG-I/MDA5-mediated IFN-I signaling pathway, is targeted and degraded by hsa-miR-146a-5p. As TRAF6 is necessary for IFN-β induction, inhibition of this protein attenuates IFN-β signaling. Taken together, the results from this study indicated that HAV disrupts RIG-I/MDA5-mediated IFN-I signaling partially through the cleavage of the essential adaptor molecule TRAF6 via hsa-miR-146a-5p.