Hepatitis B virus; E3 ubiquitin ligase; Viral transcription; HBx; Episomal genome
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.
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
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.
Ferrari Paolo, Strubin Michel (2015), Uncoupling histone turnover from transcription-associated histone H3 modifications., in Nucleic Acids Research
, 43(8), 3972-85.
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.
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.