Hepatitis C virus infection restricts human LINE-1 retrotransposition in hepatoma cells

Abstract

LINE-1 (L1) retrotransposons are autonomous transposable elements that can affect gene expression and genome integrity. Potential consequences of exogenous viral infections for L1 activity have not been studied to date. Here, we report that hepatitis C virus (HCV) infection causes a significant increase of endogenous L1-encoded ORF1 protein (L1ORF1p) levels and translocation of L1ORF1p to HCV assembly sites at lipid droplets. HCV replication interferes with retrotransposition of engineered L1 reporter elements, which correlates with HCV RNA-induced formation of stress granules and can be partially rescued by knockdown of the stress granule protein G3BP1. Upon HCV infection, L1ORF1p localizes to stress granules, associates with HCV core in an RNA-dependent manner and translocates to lipid droplets. While HCV infection has a negative effect on L1 mobilization, L1ORF1p neither restricts nor promotes HCV infection. In summary, our data demonstrate that HCV infection causes an increase of endogenous L1 protein levels and that the observed restriction of retrotransposition of engineered L1 reporter elements is caused by sequestration of L1ORF1p in HCV-induced stress granules.

The Role of Transposable Elements in Sexual Development

“…The artificial inhibition of stress granule formation increased open reading frame 1 protein (ORF1p), an RNA-binding chaperone encoded by L1 ( Chesnokova et al, 2022 ). This negative role of stress granules on ORF1p was, in the same fashion, observed in the context of hepatitis C virus infection ( Schöbel et al, 2021 ). In tandem with these, this appeared to be the case in cancer cells too.…”

Factors Regulating the Activity of LINE1 Retrotransposons

“…L1 activity can also be suppressed by viruses. For example, it has been shown that HIV-1 suppresses L1 retrotransposition by binding to ORF2 using the Vpr protein included in HIV-1 [321] or the hepatitis C virus, which provokes the formation of ORF1 stress granules [322]. Defects in many L1 inhibitory antiviral immune response genes are associated with autoimmune diseases such as Aicardi-Goutières syndrome [323].…”

SARS‐CoV‐2‐encoded inhibitors of human LINE‐1 retrotransposition

“… 30 A recent study also showed that HCV infection results in decreased L1 activity via the redistribution of L1 ORF1p to HCV‐assembly sites in lipid droplets. 49 Further, we recently found that infection with different enteroviruses leads to the suppression of L1 mobility owing to the synergistic effects of diverse viral accessory proteins. 50 Herein, we demonstrated that the newly emerging virus SARS‐CoV‐2 has gained the ability to interfere with L1 activity, which also implies that other coronaviruses have potential L1‐inhibitory features.…”