Inactivating a cellular intrinsic immune defense mediated by Daxx is the mechanism through which the human cytomegalovirus pp71 protein stimulates viral immediate-early gene expression.
Human cytomegalovirus (HCMV) masterfully evades adaptive and innate immune responses, allowing infection to be maintained and periodically reactivated for the life of the host. Here we show that cells also possess an intrinsic immune defense against HCMV that is disarmed by the virus. In HCMV-infected cells, the promyelocytic leukemia nuclear body (PML-NB) protein Daxx silences viral immediate-early gene expression through the action of a histone deacetylase. However, this antiviral tactic is efficiently neutralized by the viral pp71 protein, which is incorporated into virions, delivered to cells upon infection, and mediates the proteasomal degradation of Daxx. This work demonstrates the mechanism through which pp71 activates viral immediate-early gene expression in HCMV-infected cells. Furthermore, it provides insight into how a PML-NB protein institutes an intrinsic immune defense against a DNA virus and how HCMV pp71 inactivates this defense.
Saffert
Ryan T
RT
Institute for Molecular Virology, and McArdle Laboratory for Cancer Research, University of Wisconsin--Madison, 1525 Linden Drive, Madison, Wisconsin 53706, USA.
Kalejta
Robert F
RF
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D017781:Genes, Immediate-Early; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D014764:Viral Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D014764:Viral Proteins; C051298:cytomegalovirus phosphoprotein 71kDa; C067713:lactacystin; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine