期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2214911119
关键词
hepatitisCvirus; miR-122; ELAVL1; HuR; PLK1; rigosertib
资金
- National Cancer Center Korea [NCC-2010273, NCC-2010320, NCC-2211640]
- KRIBB Research Initiative Program [KGM1062211, KGS1182221, KGM1402211]
- National Research Foundation of Korea (NRF) - Ministry of Science and ICT [NRF-2017R1A2B4008257, NRF-2019R1A2C1089145, NRF-2022R1A2B5B01001914, NRF-2020R1A2C2012347]
This study identifies the regulatory role of PLK1-ELAVL1/HuR-miR-122 signaling in HCV proliferation and suggests that targeting this host cell signaling pathway could be a useful therapeutic approach for treating HCV and HCV-associated diseases.
The liver-specific microRNA, miR-122, plays an essential role in the propagation of hepatitis C virus (HCV) by binding directly to the 5 '-end of its genomic RNA. Despite its significance for HCV proliferation, the host factors responsible for regulating miR-122 remain largely unknown. In this study, we identified the cellular RNA-binding protein, ELAVL1/HuR (embryonic lethal-abnormal vision-like 1/human antigen R), as critically contributing to miR-122 biogenesis by strong binding to the 3 '-end of miR-122. The availability of ELAVL1/HuR was highly correlated with HCV proliferation in replicon, infectious, and chronically infected patient conditions. Furthermore, by screening a kinase inhibitor library, we identified rigosertib, an anticancer agent under clinical trials, as having both miR-122-modulating and anti-HCV activities that were mediated by its ability to target polo-like kinase 1 (PLK1) and subsequently modulate ELAVL1/HuR-miR-122 signaling. The expression of PLK1 was also highly correlated with HCV prolif-eration and the HCV positivity of HCC patients. ELAVL1/HuR-miR-122 signaling and its mediation of PLK1-dependent HCV proliferation were demonstrated by performing various rescue experiments and utilizing an HCV mutant with low dependency on miR-122. In addition, the HCV-inhibitory effectiveness of rigosertib was validated in various HCV-relevant conditions, including replicons, infected cells, and replicon-harboring mice. Rigosertib was highly effective in inhibiting the proliferation of not only wild-type HCVs, but also sofosbuvir resistance-associated substitution-bearing HCVs. Our study identifies PLK1-ELAVL1/HuR-miR-122 signaling as a regulatory axis that is critical for HCV proliferation, and suggests that a therapeutic approach targeting this host cell signaling pathway could be useful for treating HCV and HCV-associated diseases.
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