Smc5/6 antagonims by HBx is an evolutionary-conserved function of hepatitis B
J Virol. 2018 May 30. pii: JVI.00769-18. doi: 10.1128/JVI.00769-18. [Epub ahead of print] Abdul F1, Filleton F2, Gerossier L3, Paturel A3, Hall J3, Strubin M1, Etienne L4.
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Chronic infection with hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. HBVs (family Hepadnaviridae) have been associated with mammals for millions of years. Recently, the Smc5/6 complex, known for its essential housekeeping functions in genome maintenance, was identified as an antiviral restriction factor of human HBV. The virus has, however, evolved to counteract this defense mechanism by degrading the complex via its regulatory HBx protein. Whether the antiviral activity of the Smc5/6 complex against hepadnaviruses is an important and evolutionarily conserved function is unknown. Here, we used an evolutionary and functional approach to address this question. We first performed phylogenetic and positive selection analyses of the Smc5/6 complex subunits and found that they have been conserved in primates and mammals. Yet, Smc6 showed marks of adaptive evolution, potentially reminiscent of virus-host “arms-race”. We then functionally tested the HBx from six divergent hepadnaviruses naturally infecting primates, rodents, and bats. Despite little sequence homology, we demonstrate that these HBx efficiently degraded mammalian Smc5/6 complexes, independently of the host species and of the sites under positive selection. Importantly, all HBx also rescued the replication of an HBx-deficient HBV in primary human hepatocytes. These findings point to an evolutionarily-conserved requirement for Smc5/6 inactivation by HBx, showing that the Smc5/6 antiviral activity has been an important defense mechanism against hepadnaviruses in mammals. It would be interesting to investigate whether Smc5/6 may further be a restriction factor of other yet unidentified viruses that may have driven some of its adaptation.
Importance: Infection with hepatitis B virus (HBV) led to 887000 human deaths in 2015. HBV has been co-evolving 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 “evolutionary arms-race”. Using evolution-guided functional analyses that include infections of primary human hepatocytes, we demonstrate that HBx 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 the 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.
Affiliations des auteurs:
1- Department of Microbiology and Molecular Medicine, University Medical Centre (C.M.U.)/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, Univ Lyon, Lyon, France. (co premier auteur).
3- CRCL- UMR Inserm 1052 – CNRS 5286, Lyon, France.
4- CIRI – International Center for Infectiology Research, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France firstname.lastname@example.org.