XRN1-dependent RNA homeostasis regulates hepatitis D virus

Activation of dsRNA sensing pathway following XRN1 depletion upregulates IFN production and IFN downstream pathways, leading to increases in host defenses to HDV infection. In addition XRN1 depletion increases ADAR1 expression, which increases L-HDAg levels and suppresses HDV replication. Image created in BioRender : https://BioRender.com/t73u45i

AUTHOR SUMMARY

Hepatitis D virus causes the most severe form of viral hepatitis, yet how our cells defend against this virus remains poorly understood. Although infection triggers strong immune responses, their effects on viral replication are limited. In this study, we identified XRN1, an enzyme involved in cellular RNA degradation, as an important regulator of hepatitis D virus infection. We found that loss of XRN1 causes the accumulation of double-stranded RNA, activates antiviral immune responses, and suppresses viral replication. We also observed increased RNA editing, highlighting the connection between RNA metabolism and antiviral immunity. Furthermore, we identified two previously unrecognized antiviral factors, DUSP5 and SIRPA, that contribute to controlling viral infection. Our findings reveal how cellular RNA degradation regulates antiviral defenses and suggest potential new approaches to treating chronic hepatitis D.