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Role of Activating Transcription Factor 3 in the Synthesis of Latency

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Role of Activating Transcription Factor 3 in the Synthesis of Latency Role of activating transcription factor 3 in the synthesis PNAS PLUS of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia Minfeng Shu, Te Du, Grace Zhou1, and Bernard Roizman2 Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, Chicago IL 60637 Contributed by Bernard Roizman, August 4, 2015 (sent for review July 17, 2015) A key property of herpes simplex viruses (HSVs) is their ability to rapidly deplete NGF or in medium containing both NGF and establish latent infection in sensory or autonomic ganglia and to epithelial growth factor (EGF) (9). In the former medium, ex- reactivate on physical, hormonal, or emotional stress. In latently pression of viral genes begins at ∼5 h after excision of the gan- infected ganglia, HSVs express a long noncoding RNA, a latency- glia. In medium containing NGF and EGF, the virus remains associated transcript (LAT), which plays a key role in maintaining silent for ∼18–24 h. Studies on this model revealed that in latently infected neurons, but not viral proteins. To investigate the ganglia maintained in medium containing NGF plus EGF, the events leading to reactivation, we examined the use of ganglionic virus is maintained in a dynamic equilibrium that is disrupted organ cultures that enable rapid reactivation in medium contain- by inhibitors of HDAC-1 and -4, the PI3K-AKT-mTOR and STAT3 ing antibody to nerve growth factor (NGF) or delayed reactivation pathways, or proapoptotic drugs (10, 11). Reactivation in medium in medium containing NGF and epidermal growth factor (EGF). containing anti-NGF antibody is inhibited by the expression of Here we report the discovery that activating transcription factor 3 REST or by a p300/CBP inhibitor (11, 12). Perhaps more sig- (ATF3), a stress response protein, profoundly affects the interac- nificant for reactivation, in neurons all genes are expressed at once tion of HSV with its host. Specifically, (i) ATF3 is induced by stress, rather than sequentially in a coordinated fashion as is seen in in- such as inhibition of protein synthesis or infection; (ii) in infected fected cells at the portal of entry. cells, ATF3 enhances the accumulation of LAT by acting on the The present study emanated from an attempt to identify the MICROBIOLOGY response elements in the promoter of the LAT precursor RNA; neuronal genes whose expression maintains the virus in a latent (iii) ATF3 is induced nearly 100-fold in ganglionic organ cultures; state. In this study, we compared by microarray analyses RNA and (iv) ATF3 plays a key role in the maintenance of the latent transcripts in freshly excised ganglia with those of ganglia in- state, inasmuch as expression of ATF3 bereft of the C-terminal cubated for 5 h or 11 h in medium containing anti-NGF antibody activation domain acts as a dominant negative factor, inducing and medium containing NGF plus EGF. The cellular gene that HSV gene expression in ganglionic organ cultures harboring latent attracted our attention was that of ATF3, because its mRNA virus and incubated in medium containing NGF and EGF. Thus, ATF3 is increased nearly 100-fold both in ganglia incubated in medium a component of a cluster of cellular proteins that together with LAT containing anti-NGF and in medium containing NGF plus EGF. maintain the integrity of the neurons harboring latent virus. We found that ATF3 enhances the accumulation of LAT in in- fected cells in culture and plays a role in the maintenance of HSV-1 stress response | adenylate-uridylate–rich mRNA | reactivation in a latent state. ATF3 is a member of the ATF/CREB family of transcriptional ollowing infection at a portal of entry, usually the mouth or factors (13, 14). The current consensus holds that ATF3 is an Fgenitals, herpes simplex virus (HSV)-1 or HSV-2 infect sen- immediate early-response gene, a regulator of stress response, sory nerve endings and are transported retrograde to the neu- and a factor in determining cell fate (15). ATF3 binds to a cAMP ronal nucleus, where they establish a silent or “latent” infection response element (CRE) with the canonical sequence 5′-TGAC- (1). Characteristically, during the latent state, neurons accumu- GTCA-3′ in the form of homodimers or heterodimers with other late a 1.5- or 2-kb noncoding RNA known as latency-associated members of the ATF/CREB family. HSV-1 DNA contains eight transcript (LAT) (2–5). LAT is a stable intron derived from a much longer precursor RNA (pLAT) (3, 6). In a fraction of Significance neurons infected with HSV-1, the virus reactivates and is trans- ported anterograde to a site at or near the portal of entry, where A major unresolved issue confronting infectious diseases is the it replicates and becomes available for transmission to another mechanism by which virulent, potentially lethal viruses remain individual by physical tissue contact (7, 8). Knowledge is scant silent (latent) in selected cells in the human body until induced regarding the mechanisms by which HSV-1, a potentially virulent to replicate and spread in response to stress. The establishment virus, can remain silent in neurons for the life of the host or of latent infection by herpes simplex viruses in sensory or au- reactivate from latency. The model organism closest to the hu- tonomic neurons is a common event in a large fraction of the man is the mouse, a model system that does not lend itself human population. Here we report that activating transcription readily to molecular analyses of events occurring in the sensory factor 3 (ATF3) is induced by stress both in infected cells in ganglia. At the other extreme, neuronal cultures harboring HSV-1 culture and in ganglia harboring latent virus. The function silenced by drugs might not reflect the natural mechanisms by which of ATF3 is to block the reactivation of virus induced by neuro- the virus is silenced in ganglia. Moreover, in ganglia, sensory nal stress. neurons are coated by satellite cells that affect the physiology of the neuron. Author contributions: M.S., T.D., G.Z., and B.R. designed research; M.S. and T.D. per- In humans, mice, and rabbits, reactivation follows stimulation formed research; M.S., T.D., and B.R. analyzed data; and B.R. wrote the paper. or a reversible or irreversible injury (1). In an attempt to probe The authors declare no conflict of interest. the events occurring after injury, we developed a ganglionic or- 1Present address: Sino-French Hoffman Institute of Immunology, Guangzhou Medical gan culture model. In this model, trigeminal ganglia are har- University, Guangzhou 510182, China. vested at 30 d after mouse corneal inoculation and incubated in 2To whom correspondence should be addressed. Email: [email protected]. medium containing anti-nerve growth factor (NGF) antibody to edu. www.pnas.org/cgi/doi/10.1073/pnas.1515369112 PNAS Early Edition | 1of7 Downloaded by guest on September 27, 2021 Fig. 1. HSV-1(F)–induced ATF3 mRNA is independent of new protein synthesis. (A) ATF3 mRNA is induced by HSV-1(F) infection. Cells (HEK293, Vero, and Hep2) were infected with HSV-1(F) at a multiplicity of infection (MOI) of 10, and then harvested at the indicated time points. ATF3 mRNA was detected by Northern blot analysis. (B) Effect of cycloheximide (CHX; 100 μg/mL) on HSV-1(F)–induced ATF3 mRNA level. Cells (HEK293, Vero, and Hep2) were infected with HSV-1(F) at an MOI of 10 in the absence or presence of CHX. 18s and 28s rRNAs served as loading controls. CRE sites, but only two of these are in a promoter, specifically in ATF3 mutants, shown schematically in Fig. 2A. As noted in the the promoter 1 of LAT (LP1) (16). Mutagenesis of the CRE1 site introductory section, ATF3 consists of an N-terminal activation (5′-CTGCGTCA-3′) proximal to the pLAT TATA box results in domain (A), followed by a repressor domain (R), a basic domain diminished levels of LAT and reduced reactivation rates in a rabbit (B), a ZIP domain (Z), and a second C-terminal activation do- model (17, 18). Those results are consistent with results of other main (A) (Fig. 2A). In these experiments, replicate cultures of studies showing that LAT protects neurons from apoptosis (19, 20). HEK293T cells were transfected with 1 μg of pcDNA or plasmids Finally, the 181-residue protein has been shown to consist of encoding intact or mutant ATF3 tagged at the N terminus with five domains: an N-terminal activation domain, a repressor do- Flag. The cells were exposed to 1 PFU of HSV-1(F) per cell at main, a basic domain, a ZIP domain essential for dimerization, 40 h after transfection and harvested at 20 h after infection. and a C-terminal activation domain (21, 22). Like many stress Northern blots of extracted LAT are shown in Fig. 2B. LAT was response genes, its mRNA contains adenylate-uridylate (AU)-rich quantified by phosphoimaging (Fig. 2E) or by quantitative RT- elements in the 3′ UTR (23). Curiously, ATF3 is not subject to PCR (qRT-PCR) (Fig. 2F). The amounts of wild type (WT) and degradation by the viral host shutoff RNase. The other AU-rich mutant ATF3 accumulating in transfected cells are shown in Fig. RNAs spared from degradation play significant roles in the biology 2D. The results show that the accumulation of LAT is enhanced of HSV (24, 25). by ATF3, and that the C-terminal activation domain is essential for the observed effect. Results ATF3 Is Induced in Untreated HSV-1–Infected Cells and in Infected Cells ATF3 Binds to CRE1 and CRE2 Sites in the Promoter of LAT Precursor Treated with Cycloheximide (100 μg/mL) at the Time of Infection.
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