宿主蛋白HuR在感染后从细胞核迁移到细胞质对于几种包括丙型肝炎病毒（HCV）在内的RNA病毒的生命周期至关重要，HCV是肝细胞癌的主要病因之一。HuR在病毒3'UTR上协助复制复合体的装配，其耗尽会阻碍病毒复制。尽管细胞质中的HuR对于HCV的复制至关重要，但对病毒如何将HuR从细胞核移动到细胞质进行协调的过程知之甚少。我们的研究表明，两种病毒蛋白NS3和NS5A共同作用来改变HuR的核质平衡。NS3激活蛋白激酶C（PKC）-δ，后者在S318位点磷酸化HuR，引发其向细胞质的导出。NS5A使AMP激活激酶（AMPK）失活，导致通过阻断AMPK介导的进口素-α1的磷酸化和乙酰化而减少HuR的核内进口。细胞质滞留或HuR的进入可以通过AMPK活化剂或者PKC-δ抑制剂逆转。我们的发现表明，应该努力开发PKC-δ的抑制剂和AMPK的活化剂，不论其单独应用还是联合应用，以抑制HCV感染。 版权声明：© 2023 Raheja等。本文是一篇遵循创作共用授权许可协议的开放获取文章，该协议允许在任何媒介中自由使用、分发和复制原文，前提是保留原著作者和出处的署名。

Host protein HuR translocation from nucleus to cytoplasm following infection is crucial for the life cycle of several RNA viruses including hepatitis C virus (HCV), a major causative agent of hepatocellular carcinoma. HuR assists the assembly of replication-complex on the viral-3'UTR, and its depletion hampers viral replication. Although cytoplasmic HuR is crucial for HCV replication, little is known about how the virus orchestrates the mobilization of HuR into the cytoplasm from the nucleus. We show that two viral proteins, NS3 and NS5A, act co-ordinately to alter the equilibrium of the nucleo-cytoplasmic movement of HuR. NS3 activates protein kinase C (PKC)-δ, which in-turn phosphorylates HuR on S318 residue, triggering its export to the cytoplasm. NS5A inactivates AMP-activated kinase (AMPK) resulting in diminished nuclear import of HuR through blockade of AMPK-mediated phosphorylation and acetylation of importin-α1. Cytoplasmic retention or entry of HuR can be reversed by an AMPK activator or a PKC-δ inhibitor. Our findings suggest that efforts should be made to develop inhibitors of PKC-δ and activators of AMPK, either separately or in combination, to inhibit HCV infection.Copyright: © 2023 Raheja et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.