Editors' ChoiceHost-Pathogen Interactions

How stress can overcome latency

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Science Signaling  22 Dec 2015:
Vol. 8, Issue 408, pp. ec377
DOI: 10.1126/scisignal.aaf1100

Once inside a neuron, herpes simplex virus (HSV) establishes a latent infection that persists throughout the host's lifetime. During latency, the DNA genome of HSV exists in neuronal nuclei as transcriptionally silent heterochromatin (see Avgousti and Weitzman), but cellular stress can reactivate expression of the genes required for resumption of the lytic cycle and production of infective virus particles. Cliffe et al. report that signaling through the c-Jun N-terminal kinase (JNK) pathway, which is activated in response to various types of cellular stress, relieved transcriptional repression of latent HSV. The authors developed an in vitro system in which sympathetic neurons were isolated from mice, infected with HSV-1 in vitro, and treated with the antiviral drug acyclovir to establish latent infection. Application of a pharmacological inhibitor of phosphoinositide 3-kinase (PI3K) induced viral reactivation, as indicated by the transcription of viral genes. Viral reactivation was accompanied by phosphorylation (activation) of the transcription factor c-Jun, a downstream target of JNK signaling. Pharmacological inhibition of JNK signaling prevented viral reactivation in response to PI3K inhibition. Excision of sensory ganglia from latently infected mice also induced phosphorylation of c-Jun and viral reactivation but not when the explanted neurons were cultured with inhibitors of JNK signaling. Furthermore, dual leucine kinase (DLK) and JNK-interacting protein-3 (JIP-3), which trigger JNK stress signaling in neurons in response to axotomy or withdrawal of nerve growth factor, were required for HSV-1 reactivation in cultured neurons. During latency, viral gene promoters are associated with histone H3 that is methylated at Lys9 (H3K9) and Lys27 (H3K27); these repressive histone modifications must be removed for viral replication. Compounds that block H3K9 or H3K27 demethylating enzymes did not prevent the early phase of transcription of viral genes associated with reactivation, but they did prevent HSV-1 replication. JNK can mediate phosphosphorylation of histone H3 on Ser10 in vitro, a modification that allows transcriptional activation of promoters, even when histone H3 is also methylated. The abundance of histone H3 that was both methylated on Lys9 and phosphosphorylated on Ser10 at viral promoters increased upon HSV-1 reactivation, and this increase was not observed when JNK signaling was inhibited. Chromatin immunoprecipitation revealed that JNK was enriched on viral promoters during reactivation, suggesting that, in response to cellular stress, JNK directly modifies histones to allow transcription of the genes required for the initial phase of HSV-1 reactivation.

A. R. Cliffe, J. H. Arbuckle, J. L. Vogel, M. J. Geden, S. B. Rothbart, C. L. Cusack, B. D. Strahl, T. M. Kristie, M. Deshmukh, Neuronal stress pathway mediating a histone methyl/phospho switch is required for herpes simplex virus reactivation. Cell Host Microbe 18, 649–658 (2015). [PubMed]

D. C. Avgousti, M. D. Weitzman. Stress flips a chromatin switch to wake up latent virus. Cell Host Microbe 18, 639–641 (2015). [PubMed]

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