{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:04:27Z","timestamp":1760241867480,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,16]],"date-time":"2018-10-16T00:00:00Z","timestamp":1539648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["2015W729WH","2015RMNSTA"],"award-info":[{"award-number":["2015W729WH","2015RMNSTA"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007388","name":"Compagnia di San Paolo","doi-asserted-by":"publisher","award":["CSP 2016"],"award-info":[{"award-number":["CSP 2016"]}],"id":[{"id":"10.13039\/100007388","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006692","name":"Universit\u00e0 degli Studi di Torino","doi-asserted-by":"publisher","award":["LANSRILO1701","DELVRILO1701","DEAMRILO1701"],"award-info":[{"award-number":["LANSRILO1701","DELVRILO1701","DEAMRILO1701"]}],"id":[{"id":"10.13039\/501100006692","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Interleukin-1\u03b2 (IL-1\u03b2) is a key effector of the inflammasome complex in response to pathogens and danger signals. Although it is well known that assembly of the inflammasome triggers proteolytic cleavage of the biologically inactive precursor pro-IL-1\u03b2 into its mature secreted form, the mechanism by which human cytomegalovirus (HCMV) regulates IL-1\u03b2 production via the inflammasome is still poorly understood. Here, we show that the infection of human foreskin fibroblasts (HFFs) with a mutant HCMV lacking the tegument protein pp65 (v65Stop) results in higher expression levels of mature IL-1\u03b2 compared to its wild-type counterpart, suggesting that pp65 mediates HCMV immune evasion through downmodulation of IL-1\u03b2. Furthermore, we show that enhanced IL-1\u03b2 production by the v65Stop mutant is due in part to induction of DNA binding and the transcriptional activity of NF-\u03baB. Lastly, we demonstrate that HCMV infection of HFFs triggers a non-canonical IL-1\u03b2 activation pathway where caspase-8 promotes IL-1\u03b2 maturation independently of caspase-1. Altogether, our findings provide novel mechanistic insights into the interplay between HCMV and the inflammasome system and raise the possibility of targeting pp65 to treat HCMV infection.<\/jats:p>","DOI":"10.3390\/v10100567","type":"journal-article","created":{"date-parts":[[2018,10,16]],"date-time":"2018-10-16T11:07:51Z","timestamp":1539688071000},"page":"567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Viral Tegument Protein pp65 Impairs Transcriptional Upregulation of IL-1\u03b2 by Human Cytomegalovirus through Inhibition of NF-kB Activity"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7675-0762","authenticated-orcid":false,"given":"Matteo","family":"Biolatti","sequence":"first","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9336-7906","authenticated-orcid":false,"given":"Valentina","family":"Dell\u2019Oste","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7431-0875","authenticated-orcid":false,"given":"Sara","family":"Scutera","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6389-5129","authenticated-orcid":false,"given":"Francesca","family":"Gugliesi","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2578-9621","authenticated-orcid":false,"given":"Gloria","family":"Griffante","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3188-5783","authenticated-orcid":false,"given":"Marco","family":"De Andrea","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Intrinsic Immunity Unit, CAAD\u2013Center for Translational Research on Autoimmune and Allergic Disease, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiziana","family":"Musso","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3153-2865","authenticated-orcid":false,"given":"Santo","family":"Landolfo","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Britt, W.J. (2017). Congenital Human Cytomegalovirus Infection and the Enigma of Maternal Immunity. J. Virol., 91.","DOI":"10.1128\/JVI.02392-16"},{"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","first-page":"279","DOI":"10.2217\/fvl.12.8","article-title":"The immune response to human CMV","volume":"7","author":"Diamond","year":"2012","journal-title":"Future Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nri2937","article-title":"Recognition of herpesviruses by the innate immune system","volume":"11","author":"Paludan","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/bs.aivir.2014.11.003","article-title":"Innate recognition of alphaherpesvirus DNA","volume":"92","author":"Luecke","year":"2015","journal-title":"Adv. Virus Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/nyas.12458","article-title":"Mechanism of NLRP3 inflammasome activation","volume":"1319","author":"Sutterwala","year":"2014","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4806","DOI":"10.4049\/jimmunol.162.8.4806","article-title":"Human cytomegalovirus binding to human monocytes induces immunoregulatory gene expression","volume":"162","author":"Yurochko","year":"1999","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Huang, Y., Liu, L., Ma, D., Liao, Y., Lu, Y., Huang, H., Qin, W., Liu, X., and Fang, F. (2017). Human cytomegalovirus triggers the assembly of AIM2 inflammasome in THP-1-derived macrophages. J. Med. Virol.","DOI":"10.1002\/jmv.24846"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11439","DOI":"10.1073\/pnas.1534570100","article-title":"Human cytomegalovirus UL83-coded pp65 virion protein inhibits antiviral gene expression in infected cells","volume":"100","author":"Browne","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10995","DOI":"10.1128\/JVI.78.20.10995-11006.2004","article-title":"Major human cytomegalovirus structural protein pp65 (ppUL83) prevents interferon response factor 3 activation in the interferon response","volume":"78","author":"Abate","year":"2004","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Biolatti, M., Dell\u2019Oste, V., Pautasso, S., Gugliesi, F., von Einem, J., Krapp, C., Jakobsen, M.R., Borgogna, C., Gariglio, M., and De Andrea, M. (2018). Human Cytomegalovirus Tegument Protein pp65 (pUL83) Dampens Type I Interferon Production by Inactivating the DNA Sensor cGAS without Affecting STING. J. Virol., 92.","DOI":"10.1128\/JVI.01774-17"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s12985-016-0673-5","article-title":"Interaction between HCMV pUL83 and human AIM2 disrupts the activation of the AIM2 inflammasome","volume":"14","author":"Huang","year":"2017","journal-title":"Virol. J."},{"key":"ref_13","first-page":"87","article-title":"The human cytomegalovirus tegument protein pp65 (pUL83): A key player in innate immune evasion","volume":"41","author":"Biolatti","year":"2018","journal-title":"New Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.chom.2013.10.007","article-title":"Human cytomegalovirus tegument protein pUL83 inhibits IFI16-mediated DNA sensing for immune evasion","volume":"14","author":"Li","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gariano, G.R., Dell\u2019Oste, V., Bronzini, M., Gatti, D., Luganini, A., De Andrea, M., Gribaudo, G., Gariglio, M., and Landolfo, S. (2012). The intracellular DNA sensor IFI16 gene acts as restriction factor for human cytomegalovirus replication. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002498"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1128\/JVI.01818-08","article-title":"Major tegument protein pp65 of human cytomegalovirus is required for the incorporation of pUL69 and pUL97 into the virus particle and for viral growth in macrophages","volume":"83","author":"Chevillotte","year":"2009","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8238","DOI":"10.1128\/JVI.00923-16","article-title":"Regulatory Interaction between the Cellular Restriction Factor IFI16 and Viral pp65 (pUL83) Modulates Viral Gene Expression and IFI16 Protein Stability","volume":"90","author":"Biolatti","year":"2016","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1002\/eji.200939995","article-title":"The interferon-inducible gene IFI16 secretome of endothelial cells drives the early steps of the inflammatory response","volume":"40","author":"Baggetta","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6970","DOI":"10.1128\/JVI.00384-14","article-title":"Innate nuclear sensor IFI16 translocates into the cytoplasm during the early stage of in vitro human cytomegalovirus infection and is entrapped in the egressing virions during the late stage","volume":"88","author":"Gatti","year":"2014","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.4049\/jimmunol.143.10.3343","article-title":"Cytomegalovirus infection stimulates expression of monocyte-associated mediator genes","volume":"143","author":"Dudding","year":"1989","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/j.1399-302X.2007.00427.x","article-title":"Profiling of inflammatory cytokines produced by gingival fibroblasts after human cytomegalovirus infection","volume":"23","author":"Botero","year":"2008","journal-title":"Oral Microbiol. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/1742-2094-9-95","article-title":"Infection and upregulation of proinflammatory cytokines in human brain vascular pericytes by human cytomegalovirus","volume":"9","author":"Alcendor","year":"2012","journal-title":"J. Neuroinflamm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4498","DOI":"10.1128\/JVI.78.9.4498-4507.2004","article-title":"Activation of the NF-kappaB pathway in human cytomegalovirus-infected cells is necessary for efficient transactivation of the major immediate-early promoter","volume":"78","author":"DeMeritt","year":"2004","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4251","DOI":"10.1002\/j.1460-2075.1989.tb08610.x","article-title":"NF-kappa B activation of the cytomegalovirus enhancer is mediated by a viral transactivator and by T cell stimulation","volume":"8","author":"Sambucetti","year":"1989","journal-title":"EMBO J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4638","DOI":"10.1128\/jvi.71.6.4638-4648.1997","article-title":"Induction of the transcription factor Sp1 during human cytomegalovirus infection mediates upregulation of the p65 and p105\/p50 NF-kappaB promoters","volume":"71","author":"Yurochko","year":"1997","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"712","DOI":"10.4049\/jimmunol.153.2.712","article-title":"NF-kappa B regulates IL-1 beta transcription through a consensus NF-kappa B binding site and a nonconsensus CRE-like site","volume":"153","author":"Cogswell","year":"1994","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev.immunol.18.1.621","article-title":"Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity","volume":"18","author":"Karin","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"21692","DOI":"10.1038\/srep21692","article-title":"Prenatal inflammation-induced NF-\u03baB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring","volume":"6","author":"Deng","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wang, Q.-S., Xiang, Y., Cui, Y.-L., Lin, K.-M., and Zhang, X.-F. (2012). Dietary blue pigments derived from genipin, attenuate inflammation by inhibiting LPS-induced iNOS and COX-2 expression via the NF-\u03baB inactivation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034122"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/ni.2241","article-title":"A new path to IL-1\u03b2 production controlled by caspase-8","volume":"13","author":"Saleh","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ajpath.2014.08.025","article-title":"Novel roles for caspase-8 in IL-1\u03b2 and inflammasome regulation","volume":"185","author":"Gurung","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/ni.2222","article-title":"Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1\u03b2 via a noncanonical caspase-8 inflammasome","volume":"13","author":"Gringhuis","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7829","DOI":"10.1073\/pnas.141108798","article-title":"A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation","volume":"98","author":"Skaletskaya","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.4014\/jmb.1306.06023","article-title":"Mitochondria-targeted apoptosis in human cytomegalovirus-infected cells","volume":"23","author":"Lee","year":"2013","journal-title":"J. Microbiol. Biotechnol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/10\/10\/567\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:25:59Z","timestamp":1760196359000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/10\/10\/567"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,16]]},"references-count":34,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["v10100567"],"URL":"https:\/\/doi.org\/10.3390\/v10100567","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2018,10,16]]}}}