TY - JOUR
T1 - Conserved herpesvirus kinases target the DNA damage response pathway and TIP60 histone acetyltransferase to promote virus replication
AU - Li, Renfeng
AU - Zhu, Jian
AU - Xie, Zhi
AU - Liao, Gangling
AU - Liu, Jianyong
AU - Chen, Mei Ru
AU - Hu, Shaohui
AU - Woodard, Crystal
AU - Lin, Jimmy
AU - Taverna, Sean D.
AU - Desai, Prashant
AU - Ambinder, Richard F.
AU - Hayward, Gary S.
AU - Qian, Jiang
AU - Zhu, Heng
AU - Hayward, S. Diane
N1 - Funding Information:
J.Z. was supported by American Heart Association Predoctoral Fellowship 0715295U. This work is supported in part by the NIH (R01 CA30356 and R37 CA42245 to S.D.H., R21 CA138163 to S.D.H. and H.Z., RR020839 and R01 GM076102 to H.Z., and R01 EY017589 to J.Q.). We thank Jef Boeke and Seth Blackshaw for critical comments and suggestions and Ravit Arav-Boger and Ran He for assistance with HCMV infection. We also thank Lindsey Hutt-Fletcher for providing recombinant EBV-BX1 virus.
PY - 2011/10/4
Y1 - 2011/10/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chom.2011.08.013
DO - 10.1016/j.chom.2011.08.013
M3 - Article
C2 - 22018239
AN - SCOPUS:80054896036
SN - 1931-3128
VL - 10
SP - 390
EP - 400
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 4
ER -