PLK1-ELAVL1/HuR-miR-122 signaling facilitates hepatitis C virus proliferation

Abstract

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 proliferation 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.

Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na)

“…In summary, although there is still a tendency to use rigosertib as a Plk1 inhibitor [16,[25][26][27], the Plk1 inhibition mechanism for rigosertib is controversial, as there is strong evidence that this may not be the real mechanism and some alternative mechanisms have been described for the mitotic arrest phenotype.…”

Subversion of a protein–microRNA signaling pathway by hepatitis C virus

“…In PNAS, Seo et al. ( 11 ) reported that a protein–miR-122 complex is modulated by a signaling cascade to enhance HCV gene amplification. This finding is very exciting because it opens the possibility to target upstream signaling factors of miR-122 than directly miR-122.…”

“…( 13 ) observed effects of ELAVL1/HuR depletion on replication and Seo et al. ( 11 ) noted effects on translation of the viral RNA. Of course, effects of ELAVL/HuR-miR-122 depletion on translation may be a consequence of stabilization of the viral RNA by this protein–miR complex against the attack of 5′ RNA triphosphatase DUSP11 ( 15 ).…”

“…It preferentially induces mitotic arrest and apoptosis in tumor cells, with little or no effect on normal cells. In the PNAS paper ( 11 ), rigosertib not only exhibited a strong anti-HCV activity but also decreased the expression of ELAVL1/HuR and mature miR-122. These inhibitory effects were further demonstrated in mice xenografted with Huh7 cells harboring HCV replicon RNAs.…”

“…The study by Seo et al. ( 11 ) presents compelling evidence that the host protein, ELAVL1/HuR, is essential in HCV gene expression by contributing to the stability of mature miR-122. It is known that the binding of miR-122 to the 5′ end of the viral RNA induces several structural changes in the viral RNA that modulates translation, stability, and replication of both wild-type and resistance-associated variant RNAs ( 21 , 22 ).…”