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


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.

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Hepatitis A virus




Real-time reverse transcription PCR


Mitochondrial antiviral signaling protein


Tumor necrosis factor


Cytopathic effect


Type I interferon


Interferon α/β


Pattern-recognition receptors


Toll-like receptor 3


Retinoic acid-inducible gene I


Oncorhynchus mykiss melanoma differentiation associated gene 5


Interferon-associated receptor 1/2


Janus kinase/signal transducer and activator of tran-ions


Interferon-stimulated gene


Nuclear factor-κB essential modulator


Tripartite motif containing 14


TANK-binding kinase 1


IΚB kinase ε


Interferon regulatory factor 3


C-C motif chemokine ligand 5


Kaposi’s sarcoma associated herpesvirus


Ubiquitin-specific peptidase 3


Enterovirus 71


Vesicular stomatitis virus


Interleukin 1 receptor associated kinase 1/2


Herpes simplex virus


Interferon regulatory factor 1


Multiplicity of infection


Enzyme-linked immunosorbent assay

TCID50 :

Tissue culture infectious dose


Cycle threshold


Phosphate-buffered saline


RNA integrity number


Glyceraldehyde-3-phosphate dehydrogenase


RIG-I-like receptors


Nuclear factor-κB


TIR domain-containing adaptor inducing IFN-β


Mitochondrial antiviral signaling protein


Myeloid differentiation primary response gene 88


TNF receptor associated factor 6


Receptor interacting serine/threonine kinase 3


Transmembrane protein 173


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This study was supported by the Chinese Academy of Medical Science (CAMS) Innovation Fund for Medical Sciences (2017-I2M-3-022), the National Natural Science Foundation of China (NSFC grant no. 31500724), the Applied Basic Research Key Project of Yunnan (CN) (202001AS070046), and the Fund for Reserve Talents of Young and Middle-Aged Academic and Technical Leaders of Yunnan Province (2019HB043).

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Correspondence to Jiandong Shi or Yunzhang Hu.

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Mo, L., Zeng, Z., Deng, R. et al. Hepatitis A virus-induced hsa-miR-146a-5p attenuates IFN-β signaling by targeting adaptor protein TRAF6. Arch Virol 166, 789–799 (2021). https://doi.org/10.1007/s00705-021-04952-z

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