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Histone Deacetylase 4 Promotes Type I Interferon Signaling, Restricts DNA Viruses, and Is Degraded Via Vaccinia Virus Protein C6

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Histone Deacetylase 4 Promotes Type I Interferon Signaling, Restricts DNA Viruses, and Is Degraded Via Vaccinia Virus Protein C6 Histone deacetylase 4 promotes type I interferon signaling, restricts DNA viruses, and is degraded via vaccinia virus protein C6 Yongxu Lua, Jennifer H. Stuarta,1, Callum Talbot-Coopera, Shuchi Agrawal-Singhb, Brian Huntlyb, Andrei I. Smida, Joseph S. Snowdena,2, Liane Duponta, and Geoffrey L. Smitha,3 aDepartment of Pathology, University of Cambridge, CB2 1QP Cambridge, United Kingdom; and bCambridge Institute for Medical Research, University of Cambridge, CB2 0XY Cambridge, United Kingdom Edited by Thomas E. Shenk, Princeton University, Princeton, NJ, and approved April 25, 2019 (received for review September 27, 2018) Interferons (IFNs) represent an important host defense against dition of TSA (16) or the absence of HDAC1 (17, 18), HDAC2 viruses. Type I IFNs induce JAK-STAT signaling and expression of (17), or HDAC3 (19). HDAC1 coprecipitates with signal trans- IFN-stimulated genes (ISGs), which mediate antiviral activity. His- ducer and activator of transcription 1 (STAT1) and STAT2 (18). tone deacetylases (HDACs) perform multiple functions in regulat- Conversely, HDAC11 negatively regulates type I IFN signaling ing gene expression and some class I HDACs and the class IV HDAC, by controlling lysine fatty acylation of serine hydroxymethyl- HDAC11, influence type I IFN signaling. Here, HDAC4, a class II transferase 2 (SHMT2) and thereby the surface level of type I HDAC, is shown to promote type I IFN signaling and coprecipitate IFN receptor 1 (20). HDAC1, HDAC2, and HDAC3 are also with STAT2. Pharmacological inhibition of class II HDAC activity, or required for type II IFN signaling (21). knockout of HDAC4 from HEK-293T and HeLa cells, caused a de- Consistent with a role in innate immunity, HDACs can influ- α −/− fective response to IFN- . This defect in HDAC4 cells was res- ence the outcome of virus infection and consequently, some cued by reintroduction of HDAC4 or catalytically inactive HDAC4, viruses have evolved proteins to counteract or hijack HDAC ac- but not HDAC1 or HDAC5. ChIP analysis showed HDAC4 was tivity to their advantage. For example, pharmacological inhibi- recruited to ISG promoters following IFN stimulation and was needed tion of HDACs induced reactivation of quiescent genomes of MICROBIOLOGY for binding of STAT2 to these promoters. The biological importance Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein- of HDAC4 as a virus restriction factor was illustrated by the observa- Barr virus (EBV) (22–24). Similarly, HDAC inhibitors vorinostat tions that (i) the replication and spread of vaccinia virus (VACV) and + herpes simplex virus type 1 (HSV-1) were enhanced in HDAC4−/− cells and valproic acid disrupt HIV-1 latency in CD4 T cells (25, 26). ii During herpes simplex virus type 1 (HSV-1) infection, HDAC1 and inhibited by overexpression of HDAC4; and ( ) HDAC4 is tar- – geted for proteasomal degradation during VACV infection by VACV binds to the corepressor for element-1 silencing transcription protein C6, a multifunctional IFN antagonist that coprecipitates with factor/RE1 silencing transcription factor (CoREST/REST) com- HDAC4 and is necessary and sufficient for HDAC4 degradation. plex to inhibit viral gene expression, and this is countered by type I interferon signaling | STAT2 recruitment | histone deactylase 4 | Significance vaccinia virus protein C6 | immune evasion Histone deacetylases (HDACs) are regulators of host gene ex- istone deacetylases (HDACs) can repress gene expression pression. HDAC4 is shown here to have an important role in Hby deacetylating histones leading to strengthened histone– type I interferon (IFN) signaling. Here, multiple cell lines lacking DNA interactions and chromatin condensation (1). HDACs can HDAC4 had impaired responses to IFN-α and were rescued by also induce gene expression; for instance, in leukemic cells, reintroduction of HDAC4. The biological significance of HDAC4 similar numbers of genes are up- or down-regulated by the broad was demonstrated by the enhanced replication and spread of spectrum HDAC inhibitor trichostatin A (TSA) (2). Further- two DNA viruses, vaccinia virus (VACV) and herpes simplex −/− more, >1,750 proteins may be acetylated, suggesting acetylation virus type I, in HDAC4 cells, and their diminished replication has important regulatory functions beyond histone modification when HDAC4 was overexpressed. Furthermore, HDAC4 was (3). Aberrant HDAC expression or function is linked to several targeted for proteasomal degradation early after infection human diseases and cancers, and HDAC inhibitors have po- with VACV, and VACV protein C6, an inhibitor of type I IFN tential as anticancer therapeutics (4). signaling, was necessary and sufficient for this degradation. In In humans there are 18 HDACs that are classified in four sub- summary, HDAC4 is a restriction factor for large DNA viruses. families: class I (HDACs 1, 2, 3, and 8); class II HDACs, subdivided into class IIa (HDACs 4, 5, 7, and 9) and class IIb (HDACs 6 and Author contributions: Y.L., J.H.S., C.T.-C., S.A.-S., B.H., A.I.S., J.S.S., L.D., and G.L.S. de- – signed research; Y.L., J.H.S., C.T.-C., S.A.-S., A.I.S., J.S.S., and L.D. performed research; 10); class III (sirtuins 1 7); and class IV (HDAC11) (1, 4). Y.L., J.H.S., C.T.-C., S.A.-S., B.H., A.I.S., J.S.S., L.D., and G.L.S. analyzed data; and Y.L., Type I interferons (such as IFNα/β) are secreted glycoproteins J.H.S., C.T.-C., S.A.-S., A.I.S., L.D., and G.L.S. wrote the paper. that induce antimicrobial states in cells, orchestrate the inflam- The authors declare no conflict of interest. matory response to invading pathogens, and activate the adap- This article is a PNAS Direct Submission. tive immune system (5, 6). HDAC activity is important for This open access article is distributed under Creative Commons Attribution License 4.0 signaling leading to IFN expression because this is blocked by (CC BY). TSA (7). HDAC6 (8, 9), HDAC2 (10), and HDAC9 (11) were 1Present address: Global Health Security Programme, Department of Health, SW1H 0EU each reported to promote type I IFN expression. For HDAC3, London, United Kingdom. different studies using different cell types reported either acti- 2Present address: Astbury Centre for Structural Molecular Biology, Faculty of Biological vation (12) or repression (13) of IFN-β expression. On the other Sciences, University of Leeds, LS2 9JT Leeds, United Kingdom. hand, HDAC4 (14), HDAC1, and HDAC8 (8, 15) were reported 3To whom correspondence may be addressed. Email: [email protected]. to repress type I IFN expression. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. HDAC activity also affects type I IFN-stimulated gene (ISG) 1073/pnas.1816399116/-/DCSupplemental. expression as shown by impairment of ISG transcription by ad- www.pnas.org/cgi/doi/10.1073/pnas.1816399116 PNAS Latest Articles | 1of10 Downloaded by guest on September 30, 2021 HSV-1 protein ICP0 that dissociates HDAC1 from the viral (VACV). Mechanistically, HDAC4 coprecipitates with STAT2 genome (27). In human cytomegalovirus (HCMV) infection the and is recruited to IFN-stimulated response element (ISRE)- immediate early (IE) viral proteins IE1 and IE2 function to containing promoters following addition of type I IFN. Without antagonize HDAC3, thereby promoting viral replication (28, 29). HDAC4, binding of STAT2 to these promoters after IFN-α addition Interestingly, IE1 also associates with HDAC1 and hijacks its is greatly reduced. Lastly, HDAC4 is targeted for proteasomal deg- function to repress IE gene expression, thereby promoting early radation during VACV infection. VACV expresses many inhibitors and late viral gene expression (29). of innate immunity and IFN signaling (34, 35) and one of these, Although interplay between viruses and class I HDACs is well called C6, is a multifunctional IFN antagonist (36, 37). Here, C6 is established, less is known about viral interactions with members shown to coprecipitate with HDAC4 and to be necessary and of the class II HDAC family, such as HDAC4. HSV-1 protein sufficient for inducing the proteasomal degradation of HDAC4. ICP0 was reported to coprecipitate with HDAC4, however, the The targeting of HDAC4 by VACV provides biological evidence functional consequence of this is unknown (30). EBV nuclear antigen leader protein (EBNA-LP) also coprecipitates with HDAC4 of the importance of HDAC4 as a viral restriction factor. and overexpression of HDAC4 reduced reporter gene expression Results driven by an EBNA-LP–responsive promoter (31). Additionally, in EBV-infected B lymphocytes, HDAC4 is recruited by its in- HDAC Inhibitors Block Type I IFN Signaling. To investigate further teraction partner myocyte enhancer factor 2 (MEF2) to the EBV the roles of HDACs in type I IFN signaling, the effect of TSA on genome, and HDAC4 overexpression restricts gene transcription type I ISRE-dependent reporter gene expression was assessed in at the EBV immediate early gene BZLF1 promoter (32). Re- HeLa cells. Consistent with previous reports, type I IFN signaling cently, it was reported that knockdown of HDAC4 restricted IRF3 was largely inhibited by TSA (Fig. 1A). Next, an inhibitor of class phosphorylation (14) and HDAC4 knockout reduced HSV-1 II HDACs, LMK235, was used and found to also inhibit IFN- replication (33). α–induced ISRE-dependent gene expression in a dose-dependent This study reports that HDAC4 is required for type I IFN manner (Fig. 1B). In contrast, LMK235 treatment had no effect signaling and restricts the replication of HSV-1 and vaccinia virus on NF-κB–dependent luciferase expression in response to TNF-α A B C 8 NS 10 NS 8 NS ns IFN- ns IFN- TNF- ns ns 6 8 6 6 ** ** 4 4 *** 4 *** *** 2 2 2 Fold increase ISRE-Luc Fold increase NF B-Luc 0 Fold increase ISRE-Luc 0 0 TSA ( M)0 0.1 0.25 0.5 0 0.1 0.25 0.5LMK 0 0.25 0.5 1 0 0.25 0.5 1LMK 0 0.25 0.5 1 0 0.25 0.5 1 D E F G NS NS NS NS IFN- IFN- IFN- IL-1 80 150 20 mRNA 30 ns mRNA mRNA ** ** mRNA 60 *** 15 IFIT1 IFIT3 100 CCL5 OAS1 20 40 10 50 10 20 increase 5 d increase ld increase l old Fo Fold increase 0 0 F 0 Fo 0 DMSO 1 M LM K235 DMSO 1 M LM K235 DMSO 1 M LM K235 DMSO 1 M LM K235 Fig.
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