Protein tyrosine kinase Src suppresses hepatitis C virus particle release through regulation of Ndrg1

TL;DR

The Src kinase suppresses hepatitis C virus release by regulating Ndrg1, a finding with implications for patients on tyrosine kinase inhibitors.

Contribution

The study identifies a novel Src-Ndrg1 regulatory axis that negatively controls hepatitis C virus egress.

Findings

Src kinase knockout increases infectious HCV particle release without affecting replication.

Ndrg1 is a downstream effector of Src and its silencing promotes viral egress.

Src regulates Ndrg1 via the Stat3-Hif1α signaling pathway.

Abstract

Tyrosine kinases are known to regulate multiple stages of the hepatitis C virus (HCV) life cycle. We previously demonstrated that Abl kinase facilitates viral particle assembly; however, the roles of other tyrosine kinases remain largely undefined. In this study, we evaluated the antiviral potential of tyrosine kinase inhibitors (TKIs) and investigated the associated host regulatory mechanisms. Screening a panel of clinically approved TKIs in HCV-infected Huh-7.5 cells revealed that Bosutinib, a dual inhibitor of Abl and Src kinases, significantly reduced extracellular viral titers. Unexpectedly, CRISPR/Cas9-mediated knockout of Src kinase had no effect on viral replication, protein synthesis, or assembly but markedly enhanced the release of infectious particles. We further identified N-myc downstream regulated 1 (Ndrg1), a lipid metabolism regulator, as a downstream effector of Src. In Src-knockout cells, Ndrg1 expression was significantly downregulated at both the mRNA and the protein levels. Silencing Ndrg1 similarly promoted the release of infectious virions without affecting viral replication, indicating that the Src-Ndrg1 axis acts as a negative regulator of HCV egress. We further showed that Src kinase regulates Ndrg1 transcription via the Stat3-Hif1α signaling pathway. This previously unrecognized mechanism deepens our understanding of host–viral interactions and highlights a potential concern for patients with chronic HCV infection undergoing TKI-based therapies.

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