DNA methyltransferase DNMT3A associates with viral proteins and impacts HSV-1 infection.

Abstract

Viral infections can alter the cellular epigenetic landscape, through modulation of either DNA methylation profiles or chromatin remodeling enzymes and histone modifications. These changes can act to promote viral replication or host defense. Herpes simplex virus type 1 (HSV-1) is a prominent human pathogen, which relies on interactions with host factors for efficient replication and spread. Nevertheless, the knowledge regarding its modulation of epigenetic factors remains limited. Here, we used fluorescently-labeled viruses in conjunction with immunoaffinity purification and MS to study virus-virus and virus-host protein interactions during HSV-1 infection in primary human fibroblasts. We identified interactions among viral capsid and tegument proteins, detecting phosphorylation of the capsid protein VP26 at sites within its UL37-binding domain, and an acetylation within the major capsid protein VP5. Interestingly, we found a nuclear association between viral capsid proteins and the de novo DNA methyltransferase DNA (cytosine-5)-methyltransferase 3A (DNMT3A), which we confirmed by reciprocal isolations and microscopy. We show that drug-induced inhibition of DNA methyltransferase activity, as well as siRNA- and shRNA-mediated DNMT3A knockdowns trigger reductions in virus titers. Altogether, our results highlight a functional association of viral proteins with the mammalian DNA methyltransferase machinery, pointing to DNMT3A as a host factor required for effective HSV-1 infection.

• Authors: Daniell L Rowles, Yuan-Chin Tsai, Todd M Greco, Aaron E Lin, Minghao Li, Justin Yeh, Ileana M Cristea
• Journal: Proteomics (Proteomics) Vol. 15 Issue 12 Pg. 1968-82 (Jun 2015) ISSN: 1615-9861 [Electronic] Germany
• PMID: 25758154 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Capsid Proteins
• DNMT3A protein, human
• Proteome
• VP5 protein, Herpes simplex virus type 1
• Viral Proteins
• capsid protein VP26, herpes simplex virus type 1
• DNA (Cytosine-5-)-Methyltransferases
• DNA Methyltransferase 3A

Topics

• Animals
• Capsid Proteins (metabolism)
• Cells, Cultured
• Chlorocebus aethiops
• DNA (Cytosine-5-)-Methyltransferases (metabolism)
• DNA Methyltransferase 3A
• Fibroblasts (cytology, metabolism, virology)
• Herpes Simplex (metabolism, virology)
• Herpesvirus 1, Human (physiology)
• Host-Pathogen Interactions
• Humans
• Immunoblotting
• Immunoprecipitation
• Phosphorylation
• Proteome (analysis)
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• Vero Cells
• Viral Proteins (metabolism)
• Virus Replication