Conserved gammaherpesvirus kinase and histone variant H2AX facilitate gammaherpesvirus latency in vivo.
Many herpesvirus-encoded protein kinases facilitate viral lytic replication. Importantly, the role of viral kinases in herpesvirus latency is less clear. Mouse gammaherpesvirus-68 (MHV68)-encoded protein kinase orf36 facilitates lytic replication in part through activation of the host DNA damage response (DDR). Here we show that MHV68 latency was attenuated in the absence of orf36 expression. Unexpectedly, our study uncovered enzymatic activity-independent role of orf36 in the establishment of MHV68 latency following intraperitoneal route of infection. H2AX, an important DDR protein, facilitates MHV68 lytic replication and may be directly phosphorylated by orf36 during lytic infection. In this study, H2AX deficiency, whether systemic or limited to infected cells, attenuated the establishment of MHV68 latency in vivo. Thus, our work reveals viral kinase-dependent regulation of gammaherpesvirus latency and illuminates a novel link between H2AX, a component of a tumor suppressor DDR network, and in vivo latency of a cancer-associated gammaherpesvirus.
Tarakanova
Vera L
VL
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226, USA. vtarakan@mcw.edu
Stanitsa
Eleni
E
Leonardo
Steven M
SM
Bigley
Tarin M
TM
Gauld
Stephen B
SB
D000818:Animals; D001402:B-Lymphocytes / Q000821:virology; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006564:Herpesviridae / Q000201:enzymology*; D006566:Herpesviridae Infections / Q000821:virology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D017735:Virus Latency / Q000502:physiology*
D006657:Histones; D011494:Protein Kinases; D014764:Viral Proteins; C475961:gamma-H2AX protein, mouse