Activation of the stress-activated protein kinase JNK in response to herpes simplex virus-1 infection coordinates transition of BRD4 from chromosome association to transcription elongation.

The c-Jun N-terminal kinase (JNK) signaling pathway is required for herpes simplex virus 1 lytic infection and reactivation from latency. JNK signaling regulates cellular processes in response to stress through transcriptional regulation. However, the mechanisms by which JNK regulates HSV-1 infection are less defined. We show here that HSV-1 infection triggers BRD4 transition from chromosome association to transcriptional regulation for viral infection. Specifically, HSV-1 infection induces JNK activation which mediates redistribution of BRD4, an epigenetic reader protein, from chromatin-targeting to association with proteins of transcriptional regulation. BRD4 transitions to viral infection regulation by complexing with P-TEFb, a positive transcription elongation factor, and association with viral DNA. Genetic ablation or perturbation of JNK with chemical inhibitors or siRNA leads to impediment of BRD4 release and inhibition of HSV-1 infection. Both chemotherapeutic agents and irradiation are known to promote JNK activation and HSV reactivation. We show further that JNK agonist or chemotherapeutic agents known to activate JNK can enhance HSV-1 infection. Our study reveals a novel mechanism by which JNK regulates HSV-1 infection through stress-induced BRD4 function transition from host chromosome association to viral gene expression. The work links recurrent HSV infection by chemotherapeutic agents to JNK activation.