{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T02:44:25Z","timestamp":1782960265031,"version":"3.54.5"},"reference-count":109,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T00:00:00Z","timestamp":1717027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["AI130089"],"award-info":[{"award-number":["AI130089"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Repression of human cytomegalovirus (HCMV) immediate-early (IE) gene expression is a key regulatory step in the establishment and maintenance of latent reservoirs. Viral IE transcription and protein accumulation can be elevated during latency by treatment with histone deacetylase inhibitors such as valproic acid (VPA), rendering infected cells visible to adaptive immune responses. However, the latency-associated viral protein UL138 inhibits the ability of VPA to enhance IE gene expression during infection of incompletely differentiated myeloid cells that support latency. UL138 also limits the accumulation of IFN\u03b2 transcripts by inhibiting the cGAS-STING-TBK1 DNA-sensing pathway. Here, we show that, in the absence of UL138, the cGAS-STING-TBK1 pathway promotes both IFN\u03b2 accumulation and VPA-responsive IE gene expression in incompletely differentiated myeloid cells. Inactivation of this pathway by either genetic or pharmacological inhibition phenocopied UL138 expression and reduced VPA-responsive IE transcript and protein accumulation. This work reveals a link between cytoplasmic pathogen sensing and epigenetic control of viral lytic phase transcription and suggests that manipulation of pattern recognition receptor signaling pathways could aid in the refinement of MIEP regulatory strategies to target latent viral reservoirs.<\/jats:p>","DOI":"10.3390\/v16060877","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T12:19:46Z","timestamp":1717417186000},"page":"877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["cGAS-STING-TBK1 Signaling Promotes Valproic Acid-Responsive Human Cytomegalovirus Immediate-Early Transcription during Infection of Incompletely Differentiated Myeloid Cells"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6726-3954","authenticated-orcid":false,"given":"Emily R.","family":"Albright","sequence":"first","affiliation":[{"name":"Institute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin\u2014Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7116-3355","authenticated-orcid":false,"given":"Robert F.","family":"Kalejta","sequence":"additional","affiliation":[{"name":"Institute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin\u2014Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-0716-1111-1_1","article-title":"Overview of Human Cytomegalovirus Pathogenesis","volume":"Volume 2244","author":"Fulkerson","year":"2021","journal-title":"Methods in Molecular Biology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/path.4437","article-title":"The Pathogenesis of Human Cytomegalovirus","volume":"235","author":"Griffiths","year":"2015","journal-title":"J. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Crawford, L.B. (2023). Hematopoietic Stem Cells and Betaherpesvirus Latency. Front. Cell. Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1189805"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1099\/0022-1317-77-12-3099","article-title":"Detection of Endogenous Human Cytomegalovirus in CD34+ Bone Marrow Progenitors","volume":"77","author":"Mendelson","year":"1996","journal-title":"J. Gen. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/bs.aivir.2022.01.001","article-title":"The Complex Biology of Human Cytomegalovirus Latency","volume":"112","author":"Goodrum","year":"2022","journal-title":"Adv. Virus Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/cmi.2014.75","article-title":"The Immunology of Human Cytomegalovirus Latency: Could Latent Infection Be Cleared by Novel Immunotherapeutic Strategies?","volume":"12","author":"Wills","year":"2015","journal-title":"Cell. Mol. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Perera, M.R., Wills, M.R., and Sinclair, J.H. (2021). HCMV Antivirals and Strategies to Target the Latent Reservoir. Viruses, 13.","DOI":"10.3390\/v13050817"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.humimm.2004.02.014","article-title":"CD8(+) T-Cell Immunity to Cytomegalovirus","volume":"65","author":"Moss","year":"2004","journal-title":"Hum. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nri.2016.38","article-title":"T Cell Responses to Cytomegalovirus","volume":"16","author":"Klenerman","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lim, E.Y., Jackson, S.E., and Wills, M.R. (2020). The CD4+ T Cell Response to Human Cytomegalovirus in Healthy and Immunocompromised People. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.00202"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dooley, A.L., and O\u2019Connor, C.M. (2020). Regulation of the MIE Locus During HCMV Latency and Reactivation. Pathogens, 9.","DOI":"10.3390\/pathogens9110869"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1159\/000150504","article-title":"Regulation of Human Cytomegalovirus Immediate-Early Gene Expression","volume":"39","author":"Meier","year":"1996","journal-title":"Intervirology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1084\/jem.20050882","article-title":"Broadly Targeted Human Cytomegalovirus-Specific CD4+ and CD8+ T Cells Dominate the Memory Compartments of Exposed Subjects","volume":"202","author":"Sylwester","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Arvin, A., Campadelli-Fiume, G., Mocarski, E., Moore, P.S., Roizman, B., Whitley, R., and Yamanishi, K. (2007). Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis, Cambridge University Press.","DOI":"10.1017\/CBO9780511545313"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Adamson, C.S., and Nevels, M.M. (2020). Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function. Viruses, 12.","DOI":"10.3390\/v12010110"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1128\/CMR.00034-08","article-title":"Immunobiology of Human Cytomegalovirus: From Bench to Bedside","volume":"22","author":"Crough","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Matthews, S.M., Groves, I.J., and O\u2019Connor, C.M. (2023). Chromatin Control of Human Cytomegalovirus Infection. mBio, 14.","DOI":"10.1128\/mbio.00326-23"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kalejta, R.F., and Albright, E.R. (2020). Expanding the Known Functional Repertoire of the Human Cytomegalovirus Pp71 Protein. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.00095"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Collins-McMillen, D., Kamil, J., Moorman, N., and Goodrum, F. (2020). Control of Immediate Early Gene Expression for Human Cytomegalovirus Reactivation. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.00476"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00430-019-00581-1","article-title":"HCMV Latency: What Regulates the Regulators?","volume":"208","author":"Elder","year":"2019","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e00452-19","DOI":"10.1128\/JVI.00452-19","article-title":"Human Cytomegalovirus Enters the Primary CD34+ Hematopoietic Progenitor Cells Where It Establishes Latency by Macropinocytosis","volume":"93","author":"Lee","year":"2019","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e01021-19","DOI":"10.1128\/JVI.01021-19","article-title":"Cell Line Models for Human Cytomegalovirus Latency Faithfully Mimic Viral Entry by Macropinocytosis and Endocytosis","volume":"93","author":"Lee","year":"2019","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9109","DOI":"10.1128\/JVI.00827-07","article-title":"Human Cytomegalovirus Gene Expression Is Silenced by Daxx-Mediated Intrinsic Immune Defense in Model Latent Infections Established in Vitro","volume":"81","author":"Saffert","year":"2007","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5594","DOI":"10.1128\/JVI.00348-10","article-title":"Cellular and Viral Control over the Initial Events of Human Cytomegalovirus Experimental Latency in CD34+ Cells","volume":"84","author":"Saffert","year":"2010","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1073\/pnas.1816933116","article-title":"Human Cytomegalovirus G Protein-Coupled Receptor US28 Promotes Latency by Attenuating c-Fos","volume":"116","author":"Krishna","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"20860","DOI":"10.1073\/pnas.2009420117","article-title":"Activator Protein-1 Transactivation of the Major Immediate Early Locus Is a Determinant of Cytomegalovirus Reactivation from Latency","volume":"117","author":"Krishna","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1501164","DOI":"10.1126\/sciadv.1501164","article-title":"Cellular Defense against Latent Colonization Foiled by Human Cytomegalovirus UL138 Protein","volume":"1","author":"Lee","year":"2015","journal-title":"Sci. Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/mBio.02574-19","article-title":"Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency","volume":"10","author":"Elder","year":"2019","journal-title":"mBio"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e01889-19","DOI":"10.1128\/mBio.01889-19","article-title":"Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34+ Hematopoietic Progenitor Cells and Humanized NSG Mice","volume":"10","author":"Crawford","year":"2019","journal-title":"mBio"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Medica, S., Crawford, L.B., Denton, M., Min, C.-K., Jones, T.A., Alexander, T., Parkins, C.J., Diggins, N.L., Streblow, G.J., and Mayo, A.T. (2023). Proximity-Dependent Mapping of the HCMV US28 Interactome Identifies RhoGEF Signaling as a Requirement for Efficient Viral Reactivation. PLoS Pathog., 19.","DOI":"10.1371\/journal.ppat.1011682"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"001609","DOI":"10.1099\/jgv.0.001609","article-title":"Regulation of Host and Viral Promoters during Human Cytomegalovirus Latency via US28 and CTCF","volume":"102","author":"Elder","year":"2021","journal-title":"J. Gen. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"24674","DOI":"10.1038\/srep24674","article-title":"Transient Activation of Human Cytomegalovirus Lytic Gene Expression during Latency Allows Cytotoxic T Cell Killing of Latently Infected Cells","volume":"6","author":"Krishna","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2023025118","DOI":"10.1073\/pnas.2023025118","article-title":"Bromodomain Proteins Regulate Human Cytomegalovirus Latency and Reactivation Allowing Epigenetic Therapeutic Intervention","volume":"118","author":"Groves","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1093\/emboj\/21.5.1112","article-title":"Control of Cytomegalovirus Lytic Gene Expression by Histone Acetylation","volume":"21","author":"Murphy","year":"2002","journal-title":"EMBO J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e0002923","DOI":"10.1128\/jvi.00029-23","article-title":"NF\u03baB and Cyclic AMP Response Element Sites Mediate the Valproic Acid and UL138 Responsiveness of the Human Cytomegalovirus Major Immediate Early Enhancer and Promoter","volume":"97","author":"Albright","year":"2023","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1128\/JVI.75.4.1581-1593.2001","article-title":"Reactivation of the Human Cytomegalovirus Major Immediate-Early Regulatory Region and Viral Replication in Embryonal NTera2 Cells: Role of Trichostatin A, Retinoic Acid, and Deletion of the 21-Base-Pair Repeats and Modulator","volume":"75","author":"Meier","year":"2001","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13148-019-0654-9","article-title":"Control of Viral Infections by Epigenetic-Targeted Therapy","volume":"11","author":"Nehme","year":"2019","journal-title":"Clin. Epigenet."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Albright, E.R., Mickelson, C.K., and Kalejta, R.F. (2021). Human Cytomegalovirus UL138 Protein Inhibits the STING Pathway and Reduces Interferon Beta mRNA Accumulation during Lytic and Latent Infections. mBio, 12.","DOI":"10.1128\/mBio.02267-21"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/imcb.12555","article-title":"Control of Innate Immunity by the cGAS-STING Pathway","volume":"100","author":"Mosallanejad","year":"2022","journal-title":"Immunol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.chom.2016.01.010","article-title":"The cGAS-STING Defense Pathway and Its Counteraction by Viruses","volume":"19","author":"Ma","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41580-020-0244-x","article-title":"Molecular Mechanisms and Cellular Functions of cGAS-STING Signalling","volume":"21","author":"Hopfner","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e2100225118","DOI":"10.1073\/pnas.2100225118","article-title":"TBK1 Recruitment to STING Activates Both IRF3 and NF-\u03baB That Mediate Immune Defense against Tumors and Viral Infections","volume":"118","author":"Yum","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"107492","DOI":"10.1016\/j.celrep.2020.03.056","article-title":"TBK1 and IKK\u03b5 Act Redundantly to Mediate STING-Induced NF-\u03baB Responses in Myeloid Cells","volume":"31","author":"Balka","year":"2020","journal-title":"Cell Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5328","DOI":"10.1128\/JVI.00037-14","article-title":"Cytosolic-DNA-Mediated, STING-Dependent Proinflammatory Gene Induction Necessitates Canonical NF-\u03baB Activation through TBK1","volume":"88","author":"Abe","year":"2014","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/j.celrep.2019.03.098","article-title":"Modular Architecture of the STING C-Terminal Tail Allows Interferon and NF-\u03baB Signaling Adaptation","volume":"27","author":"Orzalli","year":"2019","journal-title":"Cell Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s12974-015-0319-3","article-title":"TANK-Binding Kinase 1 (TBK1) Modulates Inflammatory Hyperalgesia by Regulating MAP Kinases and NF-\u03baB Dependent Genes","volume":"12","author":"Stephan","year":"2015","journal-title":"J. Neuroinflammation"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2937","DOI":"10.15252\/embj.201488726","article-title":"Cytosolic RNA:DNA Hybrids Activate the cGAS-STING Axis","volume":"33","author":"Mankan","year":"2014","journal-title":"EMBO J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7960","DOI":"10.1128\/jvi.69.12.7960-7970.1995","article-title":"Human Cytomegalovirus IE1 and IE2 Proteins Block Apoptosis","volume":"69","author":"Zhu","year":"1995","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1128\/MCB.23.6.1885-1895.2003","article-title":"Human Cytomegalovirus Pp71 Stimulates Cell Cycle Progression by Inducing the Proteasome-Dependent Degradation of the Retinoblastoma Family of Tumor Suppressors","volume":"23","author":"Kalejta","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"848517","DOI":"10.3389\/fonc.2022.848517","article-title":"All-Trans-Retinoic Acid Combined With Valproic Acid Can Promote Differentiation in Myeloid Leukemia Cells by an Autophagy Dependent Mechanism","volume":"12","author":"Benjamin","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10309","DOI":"10.1128\/JVI.01220-16","article-title":"Canonical and Variant Forms of Histone H3 Are Deposited onto the Human Cytomegalovirus Genome during Lytic and Latent Infections","volume":"90","author":"Albright","year":"2016","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"11782","DOI":"10.1128\/JVI.01720-14","article-title":"The 19S Proteasome Activator Promotes Human Cytomegalovirus Immediate Early Gene Expression through Proteolytic and Nonproteolytic Mechanisms","volume":"88","author":"Winkler","year":"2014","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"197646","DOI":"10.1016\/j.virusres.2019.197646","article-title":"The Golgi Sorting Motifs of Human Cytomegalovirus UL138 Are Not Required for Latency Maintenance","volume":"270","author":"Gelbmann","year":"2019","journal-title":"Virus Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"9483","DOI":"10.1128\/JVI.01547-16","article-title":"Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency","volume":"90","author":"Lee","year":"2016","journal-title":"J. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1002\/jlb.59.4.555","article-title":"Differences in the State of Differentiation of THP-1 Cells Induced by Phorbol Ester and 1,25-Dihydroxyvitamin D3","volume":"59","author":"Schwende","year":"1996","journal-title":"J. Leukoc. Biol."},{"key":"ref_56","first-page":"1530","article-title":"Induction of Maturation in Cultured Human Monocytic Leukemia Cells by a Phorbol Diester","volume":"42","author":"Tsuchiya","year":"1982","journal-title":"Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.molimm.2021.05.012","article-title":"Inhibition of Histone Deacetylase 1 Suppresses Pseudorabies Virus Infection through cGAS-STING Antiviral Innate Immunity","volume":"136","author":"Guo","year":"2021","journal-title":"Mol. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Paijo, J., D\u00f6ring, M., Spanier, J., Grabski, E., Nooruzzaman, M., Schmidt, T., Witte, G., Messerle, M., Hornung, V., and Kaever, V. (2016). cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005546"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1038\/s41467-017-00833-9","article-title":"Small Molecule Inhibition of cGAS Reduces Interferon Expression in Primary Macrophages from Autoimmune Mice","volume":"8","author":"Vincent","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"7604","DOI":"10.1038\/s41598-020-64348-y","article-title":"Small Molecule Inhibition of Human cGAS Reduces Total cGAMP Output and Cytokine Expression in Cells","volume":"10","author":"Wiser","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"14136","DOI":"10.1074\/jbc.M109.000414","article-title":"Use of the Pharmacological Inhibitor BX795 to Study the Regulation and Physiological Roles of TBK1 and IkappaB Kinase Epsilon: A Distinct Upstream Kinase Mediates Ser-172 Phosphorylation and Activation","volume":"284","author":"Clark","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/s41586-018-0705-y","article-title":"Design of Amidobenzimidazole STING Receptor Agonists with Systemic Activity","volume":"564","author":"Ramanjulu","year":"2018","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"9899","DOI":"10.1128\/JVI.00640-06","article-title":"Regulation of the Transcription and Replication Cycle of Human Cytomegalovirus Is Insensitive to Genetic Elimination of the Cognate NF-\u03baB Binding Sites in the Enhancer","volume":"80","author":"Gustems","year":"2006","journal-title":"J. Virol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"110653","DOI":"10.1016\/j.celrep.2022.110653","article-title":"Temporal Dynamics of HCMV Gene Expression in Lytic and Latent Infections","volume":"39","author":"Rozman","year":"2022","journal-title":"Cell Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/s41564-023-01325-x","article-title":"Molecular Characterization of Human Cytomegalovirus Infection with Single-Cell Transcriptomics","volume":"8","author":"Schwartz","year":"2023","journal-title":"Nat. Microbiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.4049\/jimmunol.1202749","article-title":"Proteasomal Degradation of Herpes Simplex Virus Capsids in Macrophages Releases DNA to the Cytosol for Recognition by DNA Sensors","volume":"190","author":"Horan","year":"2013","journal-title":"J. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Aguirre, S., Luthra, P., Sanchez-Aparicio, M.T., Maestre, A.M., Patel, J., Lamothe, F., Fredericks, A.C., Tripathi, S., Zhu, T., and Pintado-Silva, J. (2017). Dengue Virus NS2B Protein Targets cGAS for Degradation and Prevents Mitochondrial DNA Sensing during Infection. Nat. Microbiol., 2.","DOI":"10.1038\/nmicrobiol.2017.37"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Liu, H., Zhu, Z., Xue, Q., Yang, F., Li, Z., Xue, Z., Cao, W., He, J., Guo, J., and Liu, X. (2023). Innate Sensing of Picornavirus Infection Involves cGAS-STING-Mediated Antiviral Responses Triggered by Mitochondrial DNA Release. PLoS Pathog., 19.","DOI":"10.1371\/journal.ppat.1011132"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4624","DOI":"10.1038\/s41467-019-12632-5","article-title":"Influenza A Virus M2 Protein Triggers Mitochondrial DNA-Mediated Antiviral Immune Responses","volume":"10","author":"Moriyama","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"112179","DOI":"10.1016\/j.celrep.2023.112179","article-title":"Leaked Genomic and Mitochondrial DNA Contribute to the Host Response to Noroviruses in a STING-Dependent Manner","volume":"42","author":"Jahun","year":"2023","journal-title":"Cell Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1126\/science.1232458","article-title":"Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway","volume":"339","author":"Sun","year":"2013","journal-title":"Science"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e47491","DOI":"10.7554\/eLife.47491","article-title":"Tight Nuclear Tethering of cGAS Is Essential for Preventing Autoreactivity","volume":"8","author":"Volkman","year":"2019","journal-title":"eLife"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41586-018-0629-6","article-title":"Nuclear cGAS Suppresses DNA Repair and Promotes Tumorigenesis","volume":"563","author":"Liu","year":"2018","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e102718","DOI":"10.15252\/embj.2019102718","article-title":"Chromatin-Bound cGAS Is an Inhibitor of DNA Repair and Hence Accelerates Genome Destabilization and Cell Death","volume":"38","author":"Jiang","year":"2019","journal-title":"EMBO J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"eabb8941","DOI":"10.1126\/sciadv.abb8941","article-title":"cGAS Suppresses Genomic Instability as a Decelerator of Replication Forks","volume":"6","author":"Chen","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Wu, Y., Song, K., Hao, W., Li, J., Wang, L., and Li, S. (2022). Nuclear Soluble cGAS Senses Double-Stranded DNA Virus Infection. Commun. Biol., 5.","DOI":"10.1038\/s42003-022-03400-1"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"108490","DOI":"10.1016\/j.celrep.2020.108490","article-title":"Nuclear cGAS Functions Non-Canonically to Enhance Antiviral Immunity via Recruiting Methyltransferase Prmt5","volume":"33","author":"Cui","year":"2020","journal-title":"Cell Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1126\/science.aab3628","article-title":"Transmission of Innate Immune Signaling by Packaging of cGAMP in Viral Particles","volume":"349","author":"Gentili","year":"2015","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1126\/science.1235047","article-title":"Latency-Associated Degradation of the MRP1 Drug Transporter during Latent Human Cytomegalovirus Infection","volume":"340","author":"Weekes","year":"2013","journal-title":"Science"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e00430-19","DOI":"10.1128\/JVI.00430-19","article-title":"The Membrane-Spanning Peptide and Acidic Cluster Dileucine Sorting Motif of UL138 Are Required To Downregulate MRP1 Drug Transporter Function in Human Cytomegalovirus-Infected Cells","volume":"93","author":"Gelbmann","year":"2019","journal-title":"J. Virol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1016\/j.immuni.2022.08.006","article-title":"ABCC1 Transporter Exports the Immunostimulatory Cyclic Dinucleotide cGAMP","volume":"55","author":"Maltbaek","year":"2022","journal-title":"Immunity"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1038\/ni.1932","article-title":"IFI16 Is an Innate Immune Sensor for Intracellular DNA","volume":"11","author":"Unterholzner","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"26412","DOI":"10.1074\/jbc.R115.652289","article-title":"The Emerging Role of Nuclear Viral DNA Sensors","volume":"290","author":"Diner","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_84","first-page":"5","article-title":"The Interferon-Inducible DNA-Sensor Protein IFI16: A Key Player in the Antiviral Response","volume":"38","author":"Gatti","year":"2015","journal-title":"New Microbiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"E4492","DOI":"10.1073\/pnas.1316194110","article-title":"Nuclear Interferon-Inducible Protein 16 Promotes Silencing of Herpesviral and Transfected DNA","volume":"110","author":"Orzalli","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1128\/JVI.02249-15","article-title":"Dynamic Response of IFI16 and Promyelocytic Leukemia Nuclear Body Components to Herpes Simplex Virus 1 Infection","volume":"90","author":"Everett","year":"2016","journal-title":"J. Virol."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Johnson, K.E., Bottero, V., Flaherty, S., Dutta, S., Singh, V.V., and Chandran, B. (2014). IFI16 Restricts HSV-1 Replication by Accumulating on the Hsv-1 Genome, Repressing HSV-1 Gene Expression, and Directly or Indirectly Modulating Histone Modifications. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004503"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e0019822","DOI":"10.1128\/msystems.00198-22","article-title":"The Nuclear DNA Sensor IFI16 Indiscriminately Binds to and Diminishes Accessibility of the HSV-1 Genome to Suppress Infection","volume":"7","author":"Howard","year":"2022","journal-title":"mSystems"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e2310996120","DOI":"10.1073\/pnas.2310996120","article-title":"Nuclear Interferon-Stimulated Gene Product Maintains Heterochromatin on the Herpes Simplex Viral Genome to Limit Lytic Infection","volume":"120","author":"Sodroski","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"14391","DOI":"10.1038\/ncomms14391","article-title":"IFI16 Is Required for DNA Sensing in Human Macrophages by Promoting Production and Function of cGAMP","volume":"8","author":"Laustsen","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"14392","DOI":"10.1038\/ncomms14392","article-title":"IFI16 and cGAS Cooperate in the Activation of STING during DNA Sensing in Human Keratinocytes","volume":"8","author":"Almine","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/mBio.01553-16","article-title":"Viral DNA Sensors IFI16 and Cyclic GMP-AMP Synthase Possess Distinct Functions in Regulating Viral Gene Expression, Immune Defenses, and Apoptotic Responses during Herpesvirus Infection","volume":"7","author":"Diner","year":"2016","journal-title":"mBio"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.molcel.2018.07.034","article-title":"Non-Canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-\u03baB Signaling after Nuclear DNA Damage","volume":"71","author":"Dunphy","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1128\/JVI.02507-15","article-title":"Human Cytomegalovirus US28 Is Important for Latent Infection of Hematopoietic Progenitor Cells","volume":"90","author":"Humby","year":"2015","journal-title":"J. Virol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Perera, M.R., Roche, K.L., Murphy, E.A., and Sinclair, J.H. (2022). A Viral Long Non-Coding RNA Protects against Cell Death during Human Cytomegalovirus Infection of CD14+ Monocytes. Viruses, 14.","DOI":"10.3390\/v14020246"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Perera, M.R., and Sinclair, J.H. (2022). The Human Cytomegalovirus \u03922.7 Long Non-Coding RNA Prevents Induction of Reactive Oxygen Species to Maintain Viral Gene Silencing during Latency. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911017"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Andrade, B., Jara-Guti\u00e9rrez, C., Paz-Araos, M., V\u00e1zquez, M.C., D\u00edaz, P., and Murgas, P. (2022). The Relationship between Reactive Oxygen Species and the cGAS\/STING Signaling Pathway in the Inflammaging Process. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315182"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ni921","article-title":"IKKepsilon and TBK1 Are Essential Components of the IRF3 Signaling Pathway","volume":"4","author":"Fitzgerald","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.tcb.2020.12.003","article-title":"Expanding the View of IKK: New Substrates and New Biology","volume":"31","author":"Antonia","year":"2021","journal-title":"Trends Cell Biol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Nakatsu, Y., Matsuoka, M., Chang, T.-H., Otsuki, N., Noda, M., Kimura, H., Sakai, K., Kato, H., Takeda, M., and Kubota, T. (2014). Functionally Distinct Effects of the C-Terminal Regions of IKK\u03b5 and TBK1 on Type I IFN Production. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094999"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1743-422X-2-14","article-title":"Synergistic Inhibition of Human Cytomegalovirus Replication by Interferon-Alpha\/Beta and Interferon-Gamma","volume":"2","author":"Sainz","year":"2005","journal-title":"Virol. J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3840","DOI":"10.1073\/pnas.0600007103","article-title":"A Human Cytomegalovirus Antagonist of Type I IFN-Dependent Signal Transducer and Activator of Transcription Signaling","volume":"103","author":"Paulus","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"001929","DOI":"10.1099\/jgv.0.001929","article-title":"Inhibition of Human Cytomegalovirus Replication by Interferon Alpha Can Involve Multiple Anti-Viral Factors","volume":"104","author":"Chowdhury","year":"2023","journal-title":"J. Gen. Virol."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Li, Y., Shang, W., Xiao, G., Zhang, L.-K., and Zheng, C. (2020). A Comparative Quantitative Proteomic Analysis of HCMV-Infected Cells Highlights pUL138 as a Multifunctional Protein. Molecules, 25.","DOI":"10.3390\/molecules25112520"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Zarrella, K., Longmire, P., Zeltzer, S., Collins-McMillen, D., Hancock, M., Buehler, J., Reitsma, J.M., Terhune, S.S., Nelson, J.A., and Goodrum, F. (2023). Human Cytomegalovirus UL138 Interaction with USP1 Activates STAT1 in Infection. PLoS Pathog., 19.","DOI":"10.1101\/2023.02.07.527452"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/nri1604","article-title":"Mechanisms of Type-I- and Type-II-Interferon-Mediated Signalling","volume":"5","author":"Platanias","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3389\/fimmu.2017.00029","article-title":"Canonical and Non-Canonical Aspects of JAK-STAT Signaling: Lessons from Interferons for Cytokine Responses","volume":"8","author":"Majoros","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3857","DOI":"10.1016\/j.cell.2022.09.023","article-title":"The JAK-STAT Pathway at 30: Much Learned, Much More to Do","volume":"185","author":"Philips","year":"2022","journal-title":"Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e01194-19","DOI":"10.1128\/JVI.01194-19","article-title":"Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators","volume":"93","author":"Palermo","year":"2019","journal-title":"J. Virol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/6\/877\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:41Z","timestamp":1760107841000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/6\/877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,30]]},"references-count":109,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["v16060877"],"URL":"https:\/\/doi.org\/10.3390\/v16060877","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,30]]}}}