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Role of hepatitis B virus X protein during viral infection and associated liver cancer

English title Role of hepatitis B virus X protein during viral infection and associated liver cancer
Applicant Strubin Michel
Number 149626
Funding scheme Project funding (Div. I-III)
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Molecular Biology
Start/End 01.10.2013 - 30.09.2017
Approved amount 566'971.00
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Keywords (5)

Hepatitis B virus; E3 ubiquitin ligase; Viral transcription; HBx; Episomal genome

Lay Summary (French)

Lead
L'infection par le virus de l'hépatite B (VHB) est largement répandue dans le monde. On estime à plus de 350 millions le nombre total de porteurs chroniques de ce virus. Du fait de son évolution potentielle vers le cancer du foie, l'infection chronique par le VHB pose un problème majeur de santé publique. L’efficacité limitée des traitements actuellement disponibles laisse craindre que cette situation n'ira pas en s’améliorant dans un futur proche.
Lay summary
Nos études portent sur une petite protéine régulatrice de ce virus, baptisée HBx. Cette protéine joue un rôle déterminant au cours de l’infection virale. Elle est aussi soupçonnée favoriser le développement du cancer du foie associé à l'hépatite B chronique. Cependant, les mécanismes moléculaires mis en jeu restent inconnus. Nos travaux ont établi qu’une fonction essentielle de la protéine HBx est de permettre la transcription du génome viral. Deux observations indiquent qu’HBx accomplit cette tâche par un mécanisme inhabituel. Premièrement, l’activité stimulatrice de HBx nécessite son interaction avec une E3 ubiquitine ligase, une machinerie cellulaire capable de détruire des protéines qui lui sont présentées. Deuxièmement, HBx n’exerce un effet stimulateur que sur des matrices ADN extrachromosomiques. Cette dernière particularité est d’intérêt, puisqu’au contraire des rétrovirus, comme le virus du SIDA, qui insèrent leur génome dans les chromosomes de la cellule infectée, VHB maintient son génome sous la forme d’un ADN circulaire extrachromosomique. Ces observations suggèrent un modèle selon lequel les cellules produisent un facteur antiviral capable de détecter l’ADN extrachromosomique du VHB et de bloquer sa transcription. HBx, en guidant ce facteur vers la E3 ligase, dicterait sa destruction et de ce fait permettrait la transcription virale. En accord avec cette hypothèse, nous venons d’identifier une protéine cellulaire qu’HBx est capable de détruire et qui possède toutes les caractéristiques attendues d’un tel facteur antiviral. L’objectif de nos études futures sera de comprendre par quels mécanismes moléculaires ce facteur nouvellement identifié parvient à bloquer la transcription du génome viral, et comment HBx contrecarre cette activité. De par son mode de fonctionnement inhabituel et son rôle clé dans la réplication du VHB, HBx et sa cible permettent d’envisager une nouvelle thérapie contre l'hépatite chronique B.
Direct link to Lay Summary Last update: 31.03.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Smc5/6 Antagonism by HBx Is an Evolutionarily Conserved Function of Hepatitis B Virus Infection in Mammals
Abdul Fabien, Filleton Fabien, Gerossier Laetitia, Paturel Alexia, Hall Janet, Strubin Michel, Etienne Lucie (2018), Smc5/6 Antagonism by HBx Is an Evolutionarily Conserved Function of Hepatitis B Virus Infection in Mammals, in Journal of Virology, 92(16), e00769-18.
Identifying and characterizing interplay between hepatitis B virus X protein and Smc5/6
Livingston CM, Ramakrishnan D, Strubin M, Fletcher SP, Beran RK (2017), Identifying and characterizing interplay between hepatitis B virus X protein and Smc5/6, in Viruses, 69.
Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor.
Decorsière Adrien, Mueller Henrik, van Breugel Pieter C, Abdul Fabien, Gerossier Laetitia, Beran Rudolf K, Livingston Christine M, Niu Congrong, Fletcher Simon P, Hantz Olivier, Strubin Michel (2016), Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor., in Nature, 531(7594), 386-9.
Uncoupling histone turnover from transcription-associated histone H3 modifications.
Ferrari Paolo, Strubin Michel (2015), Uncoupling histone turnover from transcription-associated histone H3 modifications., in Nucleic Acids Research, 43(8), 3972-85.
Independent RNA polymerase II preinitiation complex dynamics and nucleosome turnover at promoter sites in vivo.
Grimaldi Yoselin, Ferrari Paolo, Strubin Michel (2014), Independent RNA polymerase II preinitiation complex dynamics and nucleosome turnover at promoter sites in vivo., in Genome research, 24(1), 117-24.

Collaboration

Group / person Country
Types of collaboration
Dr. Olivier HANTZ France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Gilead Sciences United States of America (North America)
- Publication
- Industry/business/other use-inspired collaboration

Communication with the public

Communication Title Media Place Year
Media relations: radio, television Journal télévisé de 12h45 RTS Western Switzerland 2016

Associated projects

Number Title Start Funding scheme
175781 The Smc5/6 complex as an antiviral restriction factor: how does it work and how does hepatitis B virus fight back? 01.10.2017 Project funding (Div. I-III)
175781 The Smc5/6 complex as an antiviral restriction factor: how does it work and how does hepatitis B virus fight back? 01.10.2017 Project funding (Div. I-III)
127384 Part I: Dynamics of Histone Exchange and Epigenetic Modifications during Transcription in vivo Part II: Hijacking of the DDB1 Ubiquitin Ligase by the HBV X Protein: What Role during Infection and Associated Liver Cancer? 01.10.2009 Project funding (Div. I-III)
127384 Part I: Dynamics of Histone Exchange and Epigenetic Modifications during Transcription in vivo Part II: Hijacking of the DDB1 Ubiquitin Ligase by the HBV X Protein: What Role during Infection and Associated Liver Cancer? 01.10.2009 Project funding (Div. I-III)

Abstract

Hepatitis B virus (HBV) remains a major health burden with more than 350 million chronically infected people worldwide who are at high risk of developing liver cancer. HBV encodes a small regulatory protein, known as HBx, which is essential for viral infection and has been implicated in HBV-mediated liver cancer. The basis for HBx function in either process remains elusive and is the focus of our studies. Our earlier work has established that a key role of HBx in the HBV life cycle is to promote viral gene transcription. This activity requires the binding of HBx to a cellular E3 ubiquitin ligase complex, whose function is to mark proteins for destruction. More recently, we discovered that HBx has unusual transcriptional stimulatory activity, acting only on extrachromosomal DNA templates. This is likely relevant since, in contrast to retroviruses such as the AIDS virus, the HBV genome remains as an extrachromosomal DNA circle in the infected cell. These findings led us to speculate that cells may express an antiviral factor that senses the viral DNA circle and somehow blocks its transcription. HBx would relieve the block by recruiting this factor to the E3 ligase, thereby triggering its destruction. Consistent with this prediction, we recently identified a cellular protein targeted by HBx for degradation displaying all the properties expected for such a restriction factor. We now aim to understand mechanistically how this newly identified protein blocks extrachromosomal gene expression selectively and why its destruction by the HBx protein is essential for HBV gene transcription. Because of its unusual mode of action and key role in viral transcription, the HBx protein and its newly identified cellular target may offer an opportunity for the rational design of new therapies against chronic HBV infection.
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