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

被引:31
|
作者
Abdul, Fabien [2 ]
Filleton, Fabien [1 ]
Gerossier, Laetitia [3 ]
Paturel, Alexia [3 ]
Hall, Janet [3 ]
Strubin, Michel [2 ]
Etienne, Lucie [1 ]
机构
[1] Univ Lyon, Univ Claude Bernard Lyon 1, CIRI Int Ctr Infectiol Res,INSERM, Ecole Normale Super Lyon,CNRS,U1111,UMR5308, Lyon, France
[2] Univ Geneva, Univ Med Ctr CMU, Dept Microbiol & Mol Med, Geneva, Switzerland
[3] CNRS 5286, INSERM, UMR 1052, CRCL, Lyon, France
基金
瑞士国家科学基金会;
关键词
hepatitis B virus; HBx; restriction factor; antagonism; Smc5/6; complex; virus-host interaction; evolution of virus and host genes; positive selection; X-PROTEIN; POSITIVE SELECTION; PHYLOGENETIC ANALYSIS; PRIMATE LENTIVIRUSES; RESTRICTION FACTORS; MAXIMUM-LIKELIHOOD; HUMAN HEPATOCYTES; HIV-1; VIF; NEF; REPLICATION;
D O I
10.1128/JVI.00769-18
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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. In this study, 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 a virus-host "arms race." We then functionally tested the HBx proteins from six divergent hepadnaviruses naturally infecting primates, rodents, and bats. We demonstrate that despite little sequence homology, these HBx proteins efficiently degraded mammalian Smc5/6 complexes, independently of the host species and of the sites under positive selection. Importantly, all HBx proteins 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 Smc5/6 antiviral activity has been an important defense mechanism against hepadnaviruses in mammals. It will 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 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.
引用
收藏
页数:18
相关论文
共 50 条
  • [41] Association of Reduced Renal Function with Hepatitis B Virus Infection and Elevated Alanine Aminotransferase
    Cai, Jianfang
    Fan, Xiaohong
    Mou, Lijun
    Gao, Bixia
    Liu, Xuejiao
    Li, Jinhong
    Liu, Lili
    Wang, Hdiyun
    Guo, Zengyu
    Liu, Xiaoqing
    Li, Hang
    Li, Xuemei
    Li, Xuewang
    CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2012, 7 (10): : 1561 - 1566
  • [42] Outcome of hepatitis B and C virus infection on graft function after renal transplantation
    Behzad-Behbahani, A
    Mojiri, A
    Tabei, SZ
    Farhadi-Andarabi, A
    Pouransari, R
    Yaghobi, R
    Rahsaz, M
    Banihashemi, M
    Malek-hosseini, SA
    Javid, A
    Bahador, A
    Reisjalali, A
    Behzadi, S
    Salehipour, M
    Salahl, A
    Davari, R
    Janghorban, P
    Torb, A
    Salah, AR
    TRANSPLANTATION PROCEEDINGS, 2005, 37 (07) : 3045 - 3047
  • [43] Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection
    Tavakoli, S
    Schwerin, W
    Rohwer, A
    Hoffmann, S
    Weyer, S
    Weth, R
    Meisel, H
    Diepolder, H
    Geissler, M
    Galle, PR
    Löhr, HF
    Böcher, WO
    JOURNAL OF GENERAL VIROLOGY, 2004, 85 : 2829 - 2836
  • [44] DEFICIENT SUPPRESSOR CELL-FUNCTION IN HEPATITIS-B VIRUS-INFECTION
    CHISARI, FV
    ANDERSON, DS
    FEDERATION PROCEEDINGS, 1979, 38 (03) : 1157 - 1157
  • [45] PLACENTAL HEPATITIS B VIRUS INFECTION AND MATERNAL LIVER FUNCTION IN HBSAG POSITIVE WOMEN
    Lao, Terence T.
    Chung, Man-Kin
    Cheung, Theresa K. W.
    Lau, Tat-San
    Law, Lai-Wa
    Wong, Vincent W. S.
    Chan, Henry L. Y.
    Leung, Tak-Yeung
    PLACENTA, 2013, 34 (09) : A47 - A48
  • [46] Hepatitis B virus (HBV) infection, phenotype and function of myeloid and plasmacytoid dendritic cells in patients with chronic hepatitis B.
    Tavakoli, S
    Strand, D
    Schmitt, S
    Ali, M
    Weyer, S
    Geissler, M
    Galle, PR
    Boecher, WO
    HEPATOLOGY, 2003, 38 (04) : 614A - 614A
  • [47] Akt Phosphorylation of Hepatitis C Virus NS5B Regulates Polymerase Activity and Hepatitis C Virus Infection
    Sabariegos, Rosario
    Albentosa-Gonzalez, Laura
    Palmero, Blanca
    Clemente-Casares, Pilar
    Ramirez, Eugenio
    Garcia-Crespo, Carlos
    Gallego, Isabel
    de avila, Ana Isabel
    Perales, Celia
    Domingo, Esteban
    Mas, Antonio
    FRONTIERS IN MICROBIOLOGY, 2021, 12
  • [48] Human interleukin-6 facilitates hepatitis B virus infection in vitro and in vivo
    Galun, E
    Nahor, G
    Eid, A
    Jurim, O
    Rose-John, S
    Blum, HE
    Nussbaum, O
    Ilan, E
    Daudi, N
    Shouval, D
    Reisner, Y
    Dagan, S
    VIROLOGY, 2000, 270 (02) : 299 - 309
  • [49] HEPATITIS ASSOCIATED WITH A COXSACKIE B5 VIRUS INFECTION DURING LATE PREGNANCY
    OSHAUGHNESSEY, WJ
    BUECHNER, HA
    JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1962, 179 (01): : 71 - +
  • [50] Interactions between the Nse3 and Nse4 Components of the SMC5-6 Complex Identify Evolutionarily Conserved Interactions between MAGE and EID Families
    Hudson, Jessica J. R.
    Bednarova, Katerina
    Kozakova, Lucie
    Liao, Chunyan
    Guerineau, Marc
    Colnaghi, Rita
    Vidot, Susanne
    Marek, Jaromir
    Bathula, Sreenivas R.
    Lehmann, Alan R.
    Palecek, Jan
    PLOS ONE, 2011, 6 (02):