Conserved Herpesvirus Kinases Target the DNA Damage Response Pathway and TIP60 Histone Acetyltransferase to Promote Virus Replication

Abstract

Summary 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 critical for virus replication and spread. The extent of substrate conservation and the key common cell signalling 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 anti-viral strategies.

Distinct Roles for Human Cytomegalovirus Immediate Early Proteins IE1 and IE2 in the Transcriptional Regulation of MICA and PVR/CD155 Expression

“…To gain insights into the molecular mechanisms regulating the expression of activating ligands in infected cells, we investigated the role of DDR, a host cell pathway that positively affects the expression of activating ligands (35)(36)(37)(38)(39)(40)(41)(42)(43) and that it is activated by HCMV (26,27,(29)(30)(31)(32)(33)(34). Nevertheless, in HCMV-infected HFFs, MICA, ULBP3, and PVR were still increased even when ATM, ATR, and/or DNA-PK were knocked down, thus indicating that these DDR kinases are not involved in the HCMV-mediated ligand stimulation, similar to what has been reported for murine NKG2DL during murine CMV infection (78).…”

“…As previous studies reported that HCMV manipulates the DDR (26,27,(29)(30)(31)(32)(33)(34), a pathway able to stimulate NKG2DL and DNAM-1L expression as well (35)(36)(37)(38)(39)(40)(41)(42)(43), we examined the involvement of DDR signaling in the HCMV-mediated upregulation of activating ligands using genetic and pharmacological approaches.…”

“…DDR is activated by many viruses, including HCMV, and although its functional relevance in HCMV infection has not been clarified, this virus induces DDR, including activation of ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related protein (ATR), and the downstream protein H2AX (26,27,(29)(30)(31)(32)(33)(34). Interestingly, expression of some NKG2DL and DNAM-1L can be dependent on the activation of DDR and on ATM/ATR kinases (35)(36)(37)(38)(39)(40)(41)(42)(43).…”

A viral kinase mimics S6 kinase to enhance cell proliferation

“…Herpesviral kinases are also known to phosphorylate several different members of the cellular DNA damage response pathway. Notably, the regulatory protein TIP60 is targeted by herpesvirus kinases and is known to be essential for efficient herpesvirus replication (10).…”

“…The phosphorylation targets of vPK include the cellular proteins c-Jun N-terminal kinase (JNK) and the mitogen-activated kinases MKK4 and MKK7 (8), and K-bZIP, a viral protein capable of repressing viral transcription (9). Other vPK targets modulate the cellular response to DNA damage (10) and are important for subverting type 1 IFN-mediated antiviral signaling (11). This wide repertoire of targets results from vPK localizing within both the cytoplasmic and nuclear compartments (12).…”