Smc5/6 Antagonism by HBx Is an Evolutionarily Conserved Function of Hepatitis B Virus Infection in Mammals

Author:

Abdul Fabien1,Filleton Fabien2,Gerossier Laetitia3,Paturel Alexia3,Hall Janet3,Strubin Michel1,Etienne Lucie2ORCID

Affiliation:

1. Department of Microbiology and Molecular Medicine, University Medical Centre (CMU)/University of Geneva, Geneva, Switzerland

2. CIRI—International Center for Infectiology Research, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, Lyon, France

3. CRCL-UMR Inserm 1052-CNRS 5286, Lyon, France

Abstract

Infection with hepatitis B virus (HBV) led to 887,000 human deaths in 2015. HBV has been coevolving with mammals for millions of years. Recently, the Smc5/6 complex, which has essential housekeeping functions, was identified as a restriction factor of human HBV antagonized by the regulatory HBx protein. Here we address whether the antiviral activity of Smc5/6 is an important evolutionarily conserved function. We found that all six subunits of Smc5/6 have been conserved in primates, with only Smc6 showing signatures of an “evolutionary arms race.” Using evolution-guided functional analyses that included infections of primary human hepatocytes, we demonstrated that HBx proteins from very divergent mammalian HBVs could all efficiently antagonize Smc5/6, independently of the host species and sites under positive selection. These findings show that Smc5/6 antiviral activity against HBV is an important function in mammals. They also raise the intriguing possibility that Smc5/6 may restrict other, yet-unidentified viruses.

Funder

ANR Labex ECOFECT

La Ligue Contre le Cancer

Swiss National Science Foundation

Canton of Geneva

amfAR, The Foundation for AIDS Research

Fondation pour la Recherche Médicale

Agence Nationale de Recherches sur le Sida et les Hépatites Virales

Fondation Innovations en Infectiologie

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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