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Sci. Signal., 3 January 2012
Vol. 5, Issue 205, p. ra1
[DOI: 10.1126/scisignal.2001906]

RESEARCH ARTICLES

Inhibition of PP1 Phosphatase Activity by HBx: A Mechanism for the Activation of Hepatitis B Virus Transcription

Delphine Cougot1,2*, Eric Allemand3{dagger}, Lise Rivière1,2{dagger}{ddagger}, Shirine Benhenda1,2§, Karine Duroure1,2, Florence Levillayer1,2, Christian Muchardt3, Marie-Annick Buendia1,2, and Christine Neuveut1,2{ddagger}

1 Oncogenèse et Virologie Moléculaire, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France.
2 INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France.
3 CNRS URA2578, Unité de Régulation Epigénétique, Avenir INSERM, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France.

* Present address: Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK.

{dagger} These authors contributed equally to this work.

{ddagger} Present address: Institut Pasteur, Hepacivirus et Immunité Innée, 28 rue du Dr. Roux, 75015 Paris, France.

§ Present address: INSERM U944/CNRS UMR7212, Hôpital Saint-Louis, 75010 Paris, France.

Abstract: The regulatory protein HBx is essential for hepatitis B virus (HBV) replication in vivo and for transcription of the episomal HBV genome. We previously reported that in infected cells HBx activates genes targeted by the transcription factor CREB [cyclic adenosine monophosphate (cAMP) response element–binding protein]. cAMP induces phosphorylation and activation of CREB, and CREB inactivation is promoted by protein phosphatase 1 (PP1), which binds to CREB through histone deacetylase 1 (HDAC1). We showed that CREB was recruited to HBV DNA. Phosphorylation induced by cAMP had a longer half-life when CREB was bound to the episomal HBV genome compared to when it was bound to the promoter of a host target gene not regulated by HBx, suggesting that the virus has developed a mechanism to favor its own transcription. This mechanism required HBx, which interacted with and inhibited PP1 to extend the half-life of CREB phosphorylation. Silencing of PP1 rescued replication of an HBx-deficient HBV genome, suggesting that HBx enhances viral transcription in part by neutralizing PP1 activity. Our results illustrate a previously unknown mechanism of HBV transcriptional activation by HBx in which HBx interferes with the inactivation of CREB by the PP1 and HDAC1 complex.

¶ To whom correspondence should be addressed. E-mail: christine.neuveut{at}pasteur.fr

Citation: D. Cougot, E. Allemand, L. Rivière, S. Benhenda, K. Duroure, F. Levillayer, C. Muchardt, M.-A. Buendia, C. Neuveut, Inhibition of PP1 Phosphatase Activity by HBx: A Mechanism for the Activation of Hepatitis B Virus Transcription. Sci. Signal. 5, ra1 (2012).

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