STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-? but not by interferon-?.

ABSTRACT: Interferon-? (IFN-?) and IFN-? are structurally distinct cytokines that bind to different receptors, but induce expression of similar sets of genes through Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. The difference between IFN-? and IFN-? signaling remains poorly understood. Here, using the CRISPR/Cas9 system, we examine the role of STAT1 and STAT2 in the inhibition of hepatitis C virus (HCV) replication by IFN-? and IFN-?. Treatment with IFN-? increases expression of IFN-stimulated genes (ISGs) such as double-stranded RNA-activated protein kinase (PKR) and decreases viral RNA and protein levels in HCV-infected Huh-7.5 human hepatoma cells. These responses are only partially attenuated by knockout of STAT1 but are abolished by knockout of STAT2. In contrast, the inhibition of HCV replication by IFN-? is abolished by knockout of STAT1 or STAT2. Microarray analysis reveals that IFN-? but not IFN-? can induce expression of the majority of ISGs in STAT1 knockout cells. These findings suggest that IFN-? can inhibit HCV replication through a STAT2-dependent but STAT1-independent pathway, whereas IFN-? induces ISG expression and inhibits HCV replication exclusively through a STAT1- and STAT2-dependent pathway.

SUBMITTER: Yamauchi S 

PROVIDER: S-EPMC5144079 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature