Conserved herpesvirus kinases target the DNA damage response pathway and TIP60 histone acetyltransferase to promote virus replication.
Herpesviruses, which are major human pathogens, establish life-long persistent infections. Although the α, β, and γ herpesviruses infect different tissues and cause distinct diseases, they each encode a conserved serine/threonine kinase that is critical for virus replication and spread. The extent of substrate conservation and the key common cell-signaling pathways targeted by these kinases are unknown. Using a human protein microarray high-throughput approach, we identify shared substrates of the conserved kinases from herpes simplex virus, human cytomegalovirus, Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus. DNA damage response (DDR) proteins were statistically enriched, and the histone acetyltransferase TIP60, an upstream regulator of the DDR pathway, was required for efficient herpesvirus replication. During EBV replication, TIP60 activation by the BGLF4 kinase triggers EBV-induced DDR and also mediates induction of viral lytic gene expression. Identification of key cellular targets of the conserved herpesvirus kinases will facilitate the development of broadly effective antiviral strategies.
Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
Renfeng
R
Li
Jian
J
Zhu
Zhi
Z
Xie
Gangling
G
Liao
Jianyong
J
Liu
Mei-Ru
MR
Chen
Shaohui
S
Hu
Crystal
C
Woodard
Jimmy
J
Lin
Sean D
SD
Taverna
Prashant
P
Desai
Richard F
RF
Ambinder
Gary S
GS
Hayward
Jiang
J
Qian
Heng
H
Zhu
S Diane
SD
Hayward
D017124:Conserved Sequence; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000378:metabolism*; D006564:Herpesviridae / Q000201:enzymology* / Q000502:physiology; D051548:Histone Acetyltransferases / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D046228:Microarray Analysis; D008954:Models, Biological; D040081:Protein Array Analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014779:Virus Replication
D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D017346:Protein Serine-Threonine Kinases; D045643:DNA Repair Enzymes