Title | DNA methyltransferase DNMT3A associates with viral proteins and impacts HSV-1 infection. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Rowles, DL, Tsai, Y-C, Greco, TM, Lin, AE, Li, M, Yeh, J, Cristea, IM |
Journal | Proteomics |
Volume | 15 |
Issue | 12 |
Pagination | 1968-82 |
Date Published | 2015 Jun |
ISSN | 1615-9861 |
Keywords | Animals, Capsid Proteins, Cells, Cultured, Chlorocebus aethiops, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, Fibroblasts, Herpes Simplex, Herpesvirus 1, Human, Host-Pathogen Interactions, Humans, Immunoblotting, Immunoprecipitation, Phosphorylation, Proteome, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Vero Cells, Viral Proteins, Virus Replication |
Abstract | <p>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.</p> |
DOI | 10.1002/pmic.201500035 |
Alternate Journal | Proteomics |
PubMed ID | 25758154 |
PubMed Central ID | PMC4550099 |
Grant List | DP1 DA026192 / DA / NIDA NIH HHS / United States R21HD073044 / HD / NICHD NIH HHS / United States DP1DA026192 / DA / NIDA NIH HHS / United States R21 AI102187 / AI / NIAID NIH HHS / United States R01 HL127640 / HL / NHLBI NIH HHS / United States R33 AI102187 / AI / NIAID NIH HHS / United States R21 HD073044 / HD / NICHD NIH HHS / United States R21AI102187 / AI / NIAID NIH HHS / United States R01HL127640 / HL / NHLBI NIH HHS / United States |