Guanylate-Binding Proteins 2 and 5 Exert Broad Antiviral Activity by Inhibiting Furin-Mediated Processing of Viral Envelope Proteins

• Main Authors: Elisabeth Braun, Dominik Hotter, Lennart Koepke, Fabian Zech, Rüdiger Groß, Konstantin M.J. Sparrer, Janis A. Müller, Christian K. Pfaller, Elena Heusinger, Rebecka Wombacher, Kathrin Sutter, Ulf Dittmer, Michael Winkler, Graham Simmons, Martin R. Jakobsen, Karl-Klaus Conzelmann, Stefan Pöhlmann, Jan Münch, Oliver T. Fackler, Frank Kirchhoff, Daniel Sauter
• Format: Article
• Language: English
• Published: Elsevier 2019-05-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719305364

Summary: Guanylate-binding protein (GBP) 5 is an interferon (IFN)-inducible cellular factor reducing HIV-1 infectivity by an incompletely understood mechanism. Here, we show that this activity is shared by GBP2, but not by other members of the human GBP family. GBP2/5 decrease the activity of the cellular proprotein convertase furin, which mediates conversion of the HIV-1 envelope protein (Env) precursor gp160 into mature gp120 and gp41. Because this process primes HIV-1 Env for membrane fusion, viral particles produced in the presence of GBP2/5 are poorly infectious due to increased incorporation of non-functional gp160. Furin activity is critical for the processing of envelope glycoproteins of many viral pathogens. Consistently, GBP2/5 also inhibit Zika, measles, and influenza A virus replication and decrease infectivity of viral particles carrying glycoproteins of Marburg and murine leukemia viruses. Collectively, our results show that GPB2/5 exert broad antiviral activity by suppressing the activity of the virus-dependency factor furin. : The cellular protease furin processes numerous substrates, including the envelope proteins of many viral pathogens. Here, Braun et al. show that guanylate-binding proteins 2 and 5 are interferon-inducible restriction factors that reduce virion infectivity by inhibiting furin activity and consequently maturation of viral envelope glycoproteins. Keywords: GBPs, restriction factor, furin, HIV, influenza A virus, measles virus, Zika virus, viral envelope proteins