Identification of the Interferon-Inducible GTPase GBP1 as a Major Restriction Factor for Hepatitis E Virus

Abstract

This study aims to gain deeper insight into HEV-induced innate immunity by characterizing the crosstalk between the virus and the host factor guanylate-binding protein 1 (GBP1). We observe that the amount of GBP1 is elevated upon infection, although number of transcripts is decreased, which is explained by a prolonged protein half-life. Modulation of GBP1 levels via overexpression significantly inhibits the viral life cycle. Use of various GBP-1 mutants revealed that the antiviral effect of GBP-1 on HEV is independent from the GTPase-activity, but depends on the capacity of GBP-1 to form GBP1 homodimers. This connects GBP-1 to the autophagosomal pathway. Indeed, dimerization competent GBP1 targets the viral capsid protein to the lysosomal compartment leading to inactivation of the viral particle. Most importantly, silencing of GBP1 abolishes the antiviral effect of IFNγ on HEV. In IFNγ treated cells the virus is targeted to lysosomal structures and destroyed therein. This process depends in part on GBP1. These observations about the relevance of GBP1 for type II interferon-mediated innate immunity against HEV could be a base for tailoring novel antivirals and improvement of disease management. IMPORTANCE Although HEV represents a worldwide public health problem with 20 million infections and 44.000 death cases per year, there are still no specific antivirals available and many aspects of the viral life cycle are not well understood. Here we identify the guanylate binding protein 1 (GBP1) as a restriction factor affecting life cycle of HEV. Surprisingly, the antiviral effect of GBP1 does not depend on its GTPase function, but on its capacity to homodimerize. We revealed that GBP1 exerts its antiviral activity by targeting HEV to the lysosomal compartment where the virus is inactivated. Most importantly, we observed that the antiviral effect of interferon-γ on HEV strongly depends on GBP1. Our observation that GBP1 impairs HEV and is crucial for the antiviral effect of interferons on HEV extends understanding of host defense-mechanisms. As the interferon-system represents a universal defense-mechanism, our study could help to design novel antivirals targeting.

Functional cross-species conservation of guanylate-binding proteins in innate immunity

“…For KSHV, the transport of the viral capsid to the nucleus is hampered by disruption of the actin filaments by hGBP1 [ 38 ]. HEV is inhibited through the relocation of the capsid protein by hGBP1 to the lysosome [ 39 ]. For HCV, the observed interaction with RNA-dependent RNA polymerase NS5B could be a possible explanation for the viral restriction [ 40 ].…”

Interplay between Hepatitis E Virus and Host Cell Pattern Recognition Receptors

“…Very recently, the role of this antiviral factor against HEV was established. Authors revealed that GBP1 exerted its antiviral role by the homodimerization and independent of GTPase activity wherein GBP1 targeted virus to the lysosomal compartment to inactivate it [72].…”

Human Guanylate-Binding Protein 1 Positively Regulates Japanese Encephalitis Virus Replication in an Interferon Gamma Primed Environment

“…There are 7 GBPs in human that are involved in various cellular functions such as inhibition of cell spreading and proliferation, activation of inflammosome and antimicrobial activities against viruses, bacteria and protozoans ( Vestal and Jeyaratnam, 2011 ; Kravets et al., 2016 ; Wandel et al., 2017 ; Tretina et al., 2019 ; Yu et al., 2020 ). In addition to their established role in host resistance to bacterial and protozoal pathogens, GBPs (e.g., GBP1, GBP2 and GBP5) been have shown to have antiviral activity against human immunodeficiency virus (HIV), Zika virus (ZIKV), hepatitis C virus (HCV), classical swine fever virus (CSFV), dengue virus (DENV), murine norovirus (MNV), influenza virus, hepatitis E virus (HEV), vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) ( Anderson et al., 1999 ; Nordmann et al., 2012 ; Pan et al., 2012 ; Krapp et al., 2016 ; Li et al., 2016 ; Yu et al., 2020 ; Glitscher et al., 2021 ).…”