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Histone H2A mono-ubiquitylation and p38-MAP Kinases regulate immediate-early gene-like reactivation of latent retrovirus HTLV-1

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Title: Histone H2A mono-ubiquitylation and p38-MAP Kinases regulate immediate-early gene-like reactivation of latent retrovirus HTLV-1
Authors: Bangham, CRM
Taylor, GP
Klose, RJ
Schofield, CJ
Kulkarni, A
Item Type: Journal Article
Abstract: It is not understood how the human T cell leukemia virus human T-lymphotropic virus-1 (HTLV-1), a retrovirus, regulates the in vivo balance between transcriptional latency and reactivation. The HTLV-1 proviral plus-strand is typically transcriptionally silent in freshly isolated peripheral blood mononuclear cells from infected individuals, but after short-term ex vivo culture, there is a strong, spontaneous burst of proviral plus-strand transcription. Here, we demonstrate that proviral reactivation in freshly isolated, naturally infected primary CD4+ T cells has 3 key attributes characteristic of an immediate-early gene. Plus-strand transcription is p38-MAPK dependent and is not inhibited by protein synthesis inhibitors. Ubiquitylation of histone H2A (H2AK119ub1), a signature of polycomb repressive complex-1 (PRC1), is enriched at the latent HTLV-1 provirus, and immediate-early proviral reactivation is associated with rapid deubiquitylation of H2A at the provirus. Inhibition of deubiquitylation by the deubiquitinase (DUB) inhibitor PR619 reverses H2AK119ub1 depletion and strongly inhibits plus-strand transcription. We conclude that the HTLV-1 proviral plus-strand is regulated with characteristics of a cellular immediate-early gene, with a PRC1-dependent bivalent promoter sensitive to p38-MAPK signaling. Finally, we compare the epigenetic signatures of p38-MAPK inhibition, DUB inhibition, and glucose deprivation at the HTLV-1 provirus, and we show that these pathways act as independent checkpoints regulating proviral reactivation from latency.
Issue Date: 18-Oct-2018
Date of Acceptance: 30-Aug-2018
URI: http://hdl.handle.net/10044/1/63983
DOI: https://dx.doi.org/10.1172/jci.insight.123196
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation
Journal / Book Title: Journal of Clinical Investigation
Volume: 3
Issue: 20
Copyright Statement: © 2018, American Society for Clinical Investigation. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http:// creativecommons.org/licenses/ by/4.0/.
Sponsor/Funder: Wellcome Trust
Wellcome Trust
Funder's Grant Number: 207477
207477/Z/17/Z
Keywords: Cell stress
Epigenetics
Transcription
Virology
Publication Status: Published
Article Number: e123196
Appears in Collections:Department of Medicine
Faculty of Medicine



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