Murine gamma-herpesvirus 68 hijacks MAVS and IKKbeta to initiate lytic replication.
Upon viral infection, the mitochondrial antiviral signaling (MAVS)-IKKbeta pathway is activated to restrict viral replication. Manipulation of immune signaling events by pathogens has been an outstanding theme of host-pathogen interaction. Here we report that the loss of MAVS or IKKbeta impaired the lytic replication of gamma-herpesvirus 68 (gammaHV68), a model herpesvirus for human Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus. gammaHV68 infection activated IKKbeta in a MAVS-dependent manner; however, IKKbeta phosphorylated and promoted the transcriptional activation of the gammaHV68 replication and transcription activator (RTA). Mutational analyses identified IKKbeta phosphorylation sites, through which RTA-mediated transcription was increased by IKKbeta, within the transactivation domain of RTA. Moreover, the lytic replication of recombinant gammaHV68 carrying mutations within the IKKbeta phosphorylation sites was greatly impaired. These findings support the conclusion that gammaHV68 hijacks the antiviral MAVS-IKKbeta pathway to promote viral transcription and lytic infection, representing an example whereby viral replication is coupled to host immune activation.
Dong
Xiaonan
X
Department of Microbiology, UT Southwestern Medical Center, Dallas, Texas, USA.
Feng
Hao
H
Sun
Qinmiao
Q
Li
Haiyan
H
Wu
Ting-Ting
TT
Sun
Ren
R
Tibbetts
Scott A
SA
Chen
Zhijian J
ZJ
Feng
Pinghui
P
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D006566:Herpesviridae Infections; D054884:Host-Pathogen Interactions / Q000276:immunology*; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D018144:Rhadinovirus / Q000502:physiology*; D015533:Transcriptional Activation; D014412:Tumor Virus Infections; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; D051550:I-kappa B Kinase; C512612:MAVS protein, mouse; C496562:Ikbkb protein, mouse