Identification of the interferon-inducible GTPase GBP1 as major restriction factor for the Hepatitis E virus

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.