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Human cytomegalovirus UL29/28 protein interacts with components of the NuRD complex which promote accumulation of immediate-early RNA.

Histone deacetylation plays a pivotal role in regulating human cytomegalovirus gene expression. In this report, we have identified candidate HDAC1-interacting proteins in the context of infection by using a method for rapid immunoisolation of an epitope-tagged protein coupled with mass spectrometry. Putative interactors included multiple human cytomegalovirus-coded proteins. In particular, the interaction of pUL38 and pUL29/28 with HDAC1 was confirmed by reciprocal immunoprecipitations. HDAC1 is present in numerous protein complexes, including the HDAC1-containing nucleosome remodeling and deacetylase protein complex, NuRD. pUL38 and pUL29/28 associated with the MTA2 component of NuRD, and shRNA-mediated knockdown of the RBBP4 and CHD4 constituents of NuRD inhibited HCMV immediate-early RNA and viral DNA accumulation; together this argues that multiple components of the NuRD complex are needed for efficient HCMV replication. Consistent with a positive acting role for the NuRD elements during viral replication, the growth of pUL29/28- or pUL38-deficient viruses could not be rescued by treating infected cells with the deacetylase inhibitor, trichostatin A. Transient expression of pUL29/28 enhanced activity of the HCMV major immediate-early promoter in a reporter assay, regardless of pUL38 expression. Importantly, induction of the major immediate-early reporter activity by pUL29/28 required functional NuRD components, consistent with the inhibition of immediate-early RNA accumulation within infected cells after knockdown of RBBP4 and CHD4. We propose that pUL29/28 modifies the NuRD complex to stimulate the accumulation of immediate-early RNAs.

Pubmed ID: 20585571

Authors

  • Terhune SS
  • Moorman NJ
  • Cristea IM
  • Savaryn JP
  • Cuevas-Bennett C
  • Rout MP
  • Chait BT
  • Shenk T

Journal

PLoS pathogens

Publication Data

June 29, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA85786
  • Agency: NCI NIH HHS, Id: CA89810
  • Agency: NIDA NIH HHS, Id: DP1 DA026192
  • Agency: NIDA NIH HHS, Id: DP1 DA026192-04
  • Agency: NIDA NIH HHS, Id: DP1DA026192
  • Agency: NIGMS NIH HHS, Id: GM62427
  • Agency: NCI NIH HHS, Id: R01 CA082396
  • Agency: NIGMS NIH HHS, Id: R01 GM062427
  • Agency: NCRR NIH HHS, Id: RR00862
  • Agency: NCRR NIH HHS, Id: RR22220
  • Agency: NCRR NIH HHS, Id: U54 RR022220

Mesh Terms

  • Autoantigens
  • Blotting, Western
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Cytomegalovirus
  • Cytomegalovirus Infections
  • Fibroblasts
  • Fluorescent Antibody Technique
  • Histone Deacetylase 1
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Humans
  • Hydroxamic Acids
  • Immediate-Early Proteins
  • Immunoprecipitation
  • Luciferases
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • Promoter Regions, Genetic
  • RNA, Messenger
  • RNA, Viral
  • Repressor Proteins
  • Retinoblastoma-Binding Protein 4
  • Reverse Transcriptase Polymerase Chain Reaction
  • Viral Proteins
  • Virus Replication