XRN1-dependent RNA homeostasis regulates hepatitis D virus
- 1University of Oxford
Abstract
Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis, yet the host mechanisms restricting HDV replication remain poorly understood. Although HDV infection activates the MDA5-LGP2 pathway and induces robust interferon (IFN) responses, these antiviral programs have limited impact on viral replication. Here we identify the 5-3 exoribonuclease XRN1 as a key regulator of HDV infection. Loss of XRN1 in hepatoma cells increased double-stranded RNA (dsRNA) levels and induced interferon-stimulated genes (ISGs), including MDA5 and MAVS, and limited HDV infection. XRN1 deficiency enhanced ADAR1-mediated RNA editing, revealing a dynamic interplay between endogenous dsRNA metabolism and antiviral sensing. Inhibition of type I IFN signaling restored MDA5 expression and rescued HDV replication in XRN1-deficient cells. To identify the downstream effectors responsible for this restriction, we combined transcriptomic profiling with functional siRNA screening and identified DUSP5 and SIRPA as previously unrecognized ISGs with anti-HDV activity. Together, our findings establish XRN1 as a gatekeeper of dsRNA homeostasis that controls HDV replication through innate immune activation and reveals host antiviral effectors that may provide therapeutic opportunities for chronic hepatitis D.
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BibTeX
@misc{tsukuda2026xrn1dependent,
title = {{XRN1-dependent RNA homeostasis regulates hepatitis D virus}},
author = {S. Tsukuda and M. Boutasbih and P. A. C. Wing and A. Fedorov and X. Zhu and J. Rehwinkel and P. Balfe and J. A. McKeating},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.01.763535},
url = {https://www.biorxiv.org/content/10.64898/2026.11.01.763535v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - XRN1-dependent RNA homeostasis regulates hepatitis D virus
AU - S. Tsukuda
AU - M. Boutasbih
AU - P. A. C. Wing
AU - A. Fedorov
AU - X. Zhu
AU - J. Rehwinkel
AU - P. Balfe
AU - J. A. McKeating
PY - 2026
DA - 2026/11/01
PB - bioRxiv
DO - 10.64898/2026.11.01.763535
UR - https://www.biorxiv.org/content/10.64898/2026.11.01.763535v1
AB - Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis, yet the host mechanisms restricting HDV replication remain poorly understood. Although HDV infection activates the MDA5-LGP2 pathway and induces robust interferon (IFN) responses, these antiviral programs have limited impact on viral replication. Here we identify the 5-3 exoribonuclease XRN1 as a key regulator of HDV infection. Loss of XRN1 in hepatoma cells increased double-stranded RNA (dsRNA) levels and induced interferon-stimulated genes (ISGs), including MDA5 and MAVS, and limited HDV infection. XRN1 deficiency enhanced ADAR1-mediated RNA editing, revealing a dynamic interplay between endogenous dsRNA metabolism and antiviral sensing. Inhibition of type I IFN signaling restored MDA5 expression and rescued HDV replication in XRN1-deficient cells. To identify the downstream effectors responsible for this restriction, we combined transcriptomic profiling with functional siRNA screening and identified DUSP5 and SIRPA as previously unrecognized ISGs with anti-HDV activity. Together, our findings establish XRN1 as a gatekeeper of dsRNA homeostasis that controls HDV replication through innate immune activation and reveals host antiviral effectors that may provide therapeutic opportunities for chronic hepatitis D.
ER -