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

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

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

  1. Delphine Cougot1,2,*,
  2. Eric Allemand3,,
  3. Lise Rivière1,2,,
  4. Shirine Benhenda1,2,§,
  5. Karine Duroure1,2,
  6. Florence Levillayer1,2,
  7. Christian Muchardt3,
  8. Marie-Annick Buendia1,2, and
  9. Christine Neuveut1,2,
  1. 1Oncogenèse et Virologie Moléculaire, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France.
  2. 2INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France.
  3. 3CNRS URA2578, Unité de Régulation Epigénétique, Avenir INSERM, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France.
  1. To whom correspondence should be addressed. E-mail: christine.neuveut{at}pasteur.fr
  • * Present address: Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK.

  • These authors contributed equally to this work.

  • 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.

Citation:

D. Cougot, E. Allemand, L. Rivière, S. Benhenda, K. Duroure, F. Levillayer, C. Muchardt, M.-A. Buendia, and 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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