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: Benjamin Rauwel, Suk Min Jang, Marco Cassano, Adamandia Kapopoulou, Isabelle Barde, Didier Trono
• Journal: eLife (Elife) Vol. 4 (Apr 07 2015) ISSN: 2050-084X [Electronic] England
• PMID: 25846574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD34
• Chromosomal Proteins, Non-Histone
• Histones
• NF-kappa B
• Repressor Proteins
• Chromobox Protein Homolog 5
• Protein Methyltransferases
• Histone-Lysine N-Methyltransferase
• SETDB1 protein, human
• TRIM28 protein, human
• Tripartite Motif-Containing Protein 28
• TOR Serine-Threonine Kinases
• Lysine

Topics

• Antigens, CD34 (metabolism)
• Chromobox Protein Homolog 5
• Chromosomal Proteins, Non-Histone (metabolism)
• Cytomegalovirus (genetics, physiology)
• Genome, Viral
• Hematopoietic Stem Cells (metabolism, virology)
• Histone-Lysine N-Methyltransferase
• Histones (metabolism)
• Humans
• Lysine (metabolism)
• Methylation
• Monocytes (virology)
• NF-kappa B (metabolism)
• Phosphorylation
• Protein Methyltransferases
• Repressor Proteins (metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Tripartite Motif-Containing Protein 28
• Virus Latency (physiology)
• Virus Replication