Conserved herpesviral kinase promotes viral persistence by inhibiting the IRF-3-mediated type I interferon response.
A conserved herpesviral kinase, designated ORF36 in murine gamma-herpesvirus 68 (MHV-68), plays multiple vital roles in the viral life cycle. Here, we show by screening mutant viruses that ORF36 counteracts the antiviral type I interferon (IFN) response. ORF36 specifically binds to the activated form of interferon regulatory factor 3 (IRF-3) in the nucleus, inhibiting IRF-3 interaction with the cotranscriptional activator CBP and thereby suppressing the recruitment of RNA polymerase II to the interferon beta promoter. The anti-IFN function of ORF36 is conserved among herpesvirus subfamilies, although the conserved kinase activity is not absolutely required for this function. MHV-68 lacking ORF36 induces a greater interferon response and is attenuated in vitro and in vivo, where acute viral infection in the lung and latency in the spleen are compromised. Our data suggest that herpesviruses have evolved within their conserved kinase an anti-IFN activity critical for evasion of host immunity and for persistence.
Hwang
Seungmin
S
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Kim
Kyeong Seon
KS
Flano
Emilio
E
Wu
Ting-Ting
TT
Tong
Leming M
LM
Park
Ann N
AN
Song
Moon Jung
MJ
Sanchez
David Jesse
DJ
O'Connell
Ryan M
RM
Cheng
Genhong
G
Sun
Ren
R
D000818:Animals; D006566:Herpesviridae Infections / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors*; D007370:Interferon Type I / Q000096:biosynthesis*; D008168:Lung / Q000276:immunology / Q000821:virology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018144:Rhadinovirus / Q000235:genetics / Q000472:pathogenicity*; D013154:Spleen / Q000276:immunology / Q000821:virology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D014764:Viral Proteins; D037521:Virulence Factors; D011494:Protein Kinases