title: Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch.
abstract: Human cytomegalovirus (HCMV) is a highly prevalent pathogen that induces life-long infections notably through the establishment of latency in hematopoietic stem cells (HSC). Bouts of reactivation are normally controlled by the immune system, but can be fatal in immuno-compromised individuals such as organ transplant recipients. Here, we reveal that HCMV latency in human CD34(+) HSC reflects the recruitment on the viral genome of KAP1, a master co-repressor, together with HP1 and the SETDB1 histone methyltransferase, which results in transcriptional silencing. During lytic infection, KAP1 is still associated with the viral genome, but its heterochromatin-inducing activity is suppressed by mTOR-mediated phosphorylation. Correspondingly, HCMV can be forced out of latency by KAP1 knockdown or pharmacological induction of KAP1 phosphorylation, and this process can be potentiated by activating NFkB with TNF-α. These results suggest new approaches both to curtail CMV infection and to purge the virus from organ transplants.
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rauwel
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Suk Min
authors.initials: SM
authors.lastname: Jang
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Cassano
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Adamandia
authors.initials: A
authors.lastname: Kapopoulou
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Barde
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D016679:Genome, Viral; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000821:virology; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D009000:Monocytes / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011496:Protein Methyltransferases; D012097:Repressor Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28; D017735:Virus Latency / Q000502:physiology*; D014779:Virus Replication
chemical_list: D018952:Antigens, CD34; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D016328:NF-kappa B; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D058570:TOR Serine-Threonine Kinases; D008239:Lysine
keywords: cytomegalovirus; epigenetics; hematopoietic stem cells; human; infectious disease; microbiology
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