Abstract
The P body protein LSm1 stimulates translation and replication of hepatitis C virus (HCV). As the liver-specific microRNA-122 (miR-122) is required for HCV replication and is associated with P bodies, we investigated whether regulation of HCV by LSm1 involves miR-122. Here, we demonstrate that LSm1 contributes to activation of HCV internal ribosome entry site (IRES)-driven translation by miR-122. This role for LSm1 is specialized for miR-122 translation activation, as LSm1 depletion does not affect the repressive function of miR-122 at 3′ untranslated region (UTR) sites, or miR-122–mediated cleavage at a perfectly complementary site. We find that LSm1 does not influence recruitment of the microRNA (miRNA)-induced silencing complex to the HCV 5′UTR, implying that it regulates miR-122 function subsequent to target binding. In contrast to the interplay between miR-122 and LSm1 in translation, we find that LSm1 is not required for miR-122 to stimulate HCV replication, suggesting that miR-122 regulation of HCV translation and replication have different requirements. For the first time, we have identified a protein factor that specifically contributes to activation of HCV IRES-driven translation by miR-122, but not to other activities of the miRNA. Our results enhance understanding of the mechanisms by which miR-122 and LSm1 regulate HCV.
Highlights
Hepatitis C virus (HCV) is a major global cause of disease, with 2–3% of the population infected
In contrast to the interplay between miR-122 and LSm1 in translation, we find that LSm1 is not required for miR-122 to stimulate HCV replication, suggesting that miR-122 regulation of HCV translation and replication have different requirements
MiR-122 and LSm1 both contribute to HCV replication, at least in part by stimulating HCV translation [11,17], and both are localized to P bodies [18]
Summary
Hepatitis C virus (HCV) is a major global cause of disease, with 2–3% of the population infected. The HCV genome is $9.6 kb in length, with a single open reading frame encoding structural (core, E1, E2 and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins flanked by highly structured 50 and 30 UTRs [2]. Both UTRs are required for viral RNA replication, while the 50 UTR contains an internal ribosome entry site (IRES) that directly recruits the 40S ribosomal subunit and eukaryotic initiation factor 3 to initiate cap-independent translation of the viral polyprotein. The viral RNA first serves as a template for translation before replication takes place in association with endoplasmic reticulum–derived membranes, with the viral NS5B RNA-dependent RNA polymerase mediating synthesis of new À and+strand HCV RNA
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