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 hepatitis E virus (HEV)-induced innate immunity by characterizing the cross talk between the virus and the host factor guanylate-binding protein 1 (GBP1). We observe that the amount of GBP1 is elevated upon infection, although the number of transcripts is decreased, which is explained by a prolonged protein half-life. Modulation of GBP 1 levels via overexpression significantly inhibits the viral life cycle. Use of various GBP1 mutants revealed that the antiviral effect of GBP1 on HEV is independent from the GTPase ac-tivity but depends on the capacity of GBP1 to form homodimers. This connects GBP1 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 gamma interferon (IFN-g) on HEV. In IFN-g-treated cells, the virus is targeted to lyso-somal 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 deaths per year, there are still no specific antivirals available and many aspects of the viral life cycle are not well understood. Here, we identify guanylate binding protein 1 (GBP1) as a restriction factor affecting the 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 IFN-gamma on HEV strongly depends on GBP1. Our observation that GBP1 impairs HEV and is cru-cial for the antiviral effect of interferons on HEV extends the understanding of host defense mechanisms. As the interferon system represents a universal defense mechanism, our study could help to design novel antivirals.