{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:08:32Z","timestamp":1790791712435,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013622","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000}}],"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["R2024.123.1"],"award-info":[{"award-number":["R2024.123.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["R2024.123.1"],"award-info":[{"award-number":["R2024.123.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Freie und Hansestadt Hamburg"},{"DOI":"10.13039\/501100003107","name":"Bundesministerium f\u00fcr Gesundheit","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003107","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Human adenoviruses (HAdVs) are widespread pathogens with the capacity to manipulate host cellular pathways, including critical tumor suppressor networks. During oncogenic cell transformation, the adenoviral E1B-55K protein serves as a multifunctional viral regulator that, inter alia, modulates both p53-dependent and -independent pathways \u2013 though this function has been disputed in the context of viral infection. Here, we elucidate the dual role of E1B-55K in disrupting host defenses, focusing on its impact on p53 signaling and interferon-stimulated genes (ISGs) during infection. Using RNA-seq and follow-up experimental validation in A549 (p53 wildtype) and H1299 (p53-null) cells infected with wildtype HAdV-C5 or an E1B-55K-deficient mutant, we show that E1B-55K suppresses p53-mediated transcriptional responses. Concurrently, E1B-55K modulates ISG expression in a context-dependent manner. Our results reveal that E1B-55K leverages cellular context to optimize viral replication by targeting a host tumor suppressor and indicate interference with innate immune pathways. Our study thereby uncovers a previously underappreciated aspect of E1B-55K function during infection, offering insights into its repressive activity and solidifying its role as a multifunctional viral oncoprotein with broader implications for the HAdV replication cycle.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013622","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T18:32:31Z","timestamp":1762194751000},"page":"e1013622","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Adenovirus E1B-55K regulates p53-dependent and -independent gene expression during infection"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9871-086X","authenticated-orcid":true,"given":"Laura","family":"Seddar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"von Stromberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca D.","family":"Bertzbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Grundhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Dobner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5367-1401","authenticated-orcid":true,"given":"Wing Hang","family":"Ip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"issue":"24","key":"ppat.1013622.ref001","doi-asserted-by":"crossref","first-page":"3484","DOI":"10.1002\/1873-3468.13680","article-title":"Adenoviral strategies to overcome innate cellular responses to infection","volume":"593","author":"S-Y Sohn","year":"2019","journal-title":"FEBS Lett"},{"key":"ppat.1013622.ref002","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.coviro.2016.08.017","article-title":"Adenovirus sensing by the immune system","volume":"21","author":"S Atasheva","year":"2016","journal-title":"Curr Opin Virol"},{"issue":"9","key":"ppat.1013622.ref003","doi-asserted-by":"crossref","first-page":"996","DOI":"10.3390\/v12090996","article-title":"En Guard! The Interactions between Adenoviruses and the DNA Damage Response","volume":"12","author":"T Kleinberger","year":"2020","journal-title":"Viruses"},{"issue":"54","key":"ppat.1013622.ref004","doi-asserted-by":"crossref","first-page":"7824","DOI":"10.1038\/sj.onc.1204913","article-title":"Adenovirus E1A: remodelling the host cell, a life or death experience","volume":"20","author":"PH Gallimore","year":"2001","journal-title":"Oncogene"},{"key":"ppat.1013622.ref005","doi-asserted-by":"crossref","first-page":"200225","DOI":"10.1016\/j.tvr.2021.200225","article-title":"Almost famous: Human adenoviruses (and what they have taught us about cancer)","volume":"12","author":"TM Tessier","year":"2021","journal-title":"Tumour Virus Res"},{"issue":"3","key":"ppat.1013622.ref006","article-title":"Hacking the Cell: Network Intrusion and Exploitation by Adenovirus E1A","volume":"9","author":"CR King","year":"2018","journal-title":"mBio"},{"key":"ppat.1013622.ref007","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1101\/gad.324814.119","article-title":"Dedifferentiation by adenovirus E1A due to inactivation of Hippo pathway effectors YAP and TAZ","volume":"33","author":"NR Zemke","year":"2019","journal-title":"Genes Dev"},{"issue":"7","key":"ppat.1013622.ref008","doi-asserted-by":"crossref","first-page":"4606","DOI":"10.1128\/jvi.66.7.4606-4611.1992","article-title":"Adenovirus E1A makes two distinct contacts with the retinoblastoma protein","volume":"66","author":"N Dyson","year":"1992","journal-title":"J Virol"},{"issue":"9","key":"ppat.1013622.ref009","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1038\/cdd.2008.66","article-title":"Rb function is required for E1A-induced S-phase checkpoint activation","volume":"15","author":"A Nemajerova","year":"2008","journal-title":"Cell Death Differ"},{"issue":"15","key":"ppat.1013622.ref010","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1101\/gad.12.15.2434","article-title":"E1A signaling to p53 involves the p19(ARF) tumor suppressor","volume":"12","author":"E de Stanchina","year":"1998","journal-title":"Genes Dev"},{"issue":"24","key":"ppat.1013622.ref011","doi-asserted-by":"crossref","first-page":"3504","DOI":"10.1002\/1873-3468.13694","article-title":"The biology of the adenovirus E1B 55K protein","volume":"593","author":"P Hidalgo","year":"2019","journal-title":"FEBS Lett"},{"issue":"9","key":"ppat.1013622.ref012","doi-asserted-by":"crossref","first-page":"4000","DOI":"10.1128\/JVI.02417-08","article-title":"Adenovirus E1B 55-kilodalton protein: multiple roles in viral infection and cell transformation","volume":"83","author":"AN Blackford","year":"2009","journal-title":"J Virol"},{"issue":"12","key":"ppat.1013622.ref013","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1002\/1873-3468.13717","article-title":"Cell transformation by the adenovirus oncogenes E1 and E4","volume":"594","author":"WH Ip","year":"2020","journal-title":"FEBS Lett"},{"issue":"6373","key":"ppat.1013622.ref014","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/357082a0","article-title":"Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein","volume":"357","author":"PR Yew","year":"1992","journal-title":"Nature"},{"issue":"2","key":"ppat.1013622.ref015","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1101\/gad.8.2.190","article-title":"Adenovirus E1B oncoprotein tethers a transcriptional repression domain to p53","volume":"8","author":"PR Yew","year":"1994","journal-title":"Genes Dev"},{"issue":"2","key":"ppat.1013622.ref016","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/0042-6822(90)90148-K","article-title":"Domains required for in vitro association between the cellular p53 and the adenovirus 2 E1B 55K proteins","volume":"179","author":"CC Kao","year":"1990","journal-title":"Virology"},{"issue":"4","key":"ppat.1013622.ref017","doi-asserted-by":"crossref","first-page":"3146","DOI":"10.1128\/JVI.72.4.3146-3154.1998","article-title":"Adenovirus E1B 55K represses p53 activation in vitro","volume":"72","author":"ME Martin","year":"1998","journal-title":"J Virol"},{"issue":"5","key":"ppat.1013622.ref018","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1128\/MCB.19.5.3403","article-title":"Corepressor required for adenovirus E1B 55,000-molecular-weight protein repression of basal transcription","volume":"19","author":"ME Martin","year":"1999","journal-title":"Mol Cell Biol"},{"issue":"44","key":"ppat.1013622.ref019","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2310770120","article-title":"The human adenovirus E1B-55K oncoprotein coordinates cell transformation through regulation of DNA-bound host transcription factors","volume":"120","author":"K von Stromberg","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"ppat.1013622.ref020","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1002853","article-title":"The human adenovirus type 5 E1B 55 kDa protein obstructs inhibition of viral replication by type I interferon in normal human cells","volume":"8","author":"JS Chahal","year":"2012","journal-title":"PLoS Pathog"},{"issue":"8","key":"ppat.1013622.ref021","doi-asserted-by":"crossref","first-page":"3591","DOI":"10.1128\/JVI.02269-08","article-title":"The adenoviral E1B 55-kilodalton protein controls expression of immune response genes but not p53-dependent transcription","volume":"83","author":"DL Miller","year":"2009","journal-title":"J Virol"},{"issue":"1","key":"ppat.1013622.ref022","doi-asserted-by":"crossref","first-page":"298","DOI":"10.3390\/v2010298","article-title":"Dual Role of p53 in Innate Antiviral Immunity","volume":"2","author":"C Rivas","year":"2010","journal-title":"Viruses"},{"key":"ppat.1013622.ref023","first-page":"29","article-title":"Construction of adenovirus type 5 early region 1 and 4 virus mutants","volume":"130","author":"P Groitl","year":"2007","journal-title":"Methods Mol Med"},{"issue":"6","key":"ppat.1013622.ref024","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1008588","article-title":"Fluorescent protein tagging of adenoviral proteins pV and pIX reveals \u201clate virion accumulation compartment\u201d","volume":"16","author":"S Pfitzner","year":"2020","journal-title":"PLoS Pathog"},{"issue":"8","key":"ppat.1013622.ref025","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1016\/j.celrep.2017.05.008","article-title":"An Engineered Virus Library as a Resource for the Spectrum-wide Exploration of Virus and Vector Diversity","volume":"19","author":"W Zhang","year":"2017","journal-title":"Cell Rep"},{"issue":"16","key":"ppat.1013622.ref026","doi-asserted-by":"crossref","first-page":"6684","DOI":"10.1073\/pnas.0702158104","article-title":"Intranuclear targeting and nuclear export of the adenovirus E1B-55K protein are regulated by SUMO1 conjugation","volume":"104","author":"K Kindsm\u00fcller","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"ppat.1013622.ref027","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nmeth.4197","article-title":"Salmon provides fast and bias-aware quantification of transcript expression","volume":"14","author":"R Patro","year":"2017","journal-title":"Nat Methods"},{"issue":"12","key":"ppat.1013622.ref028","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome Biol"},{"key":"ppat.1013622.ref029","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkt439","article-title":"WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013","volume":"41","author":"J Wang","year":"2013","journal-title":"Nucleic Acids Res"},{"issue":"8","key":"ppat.1013622.ref030","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1084\/jem.20080383","article-title":"Transcriptional role of p53 in interferon-mediated antiviral immunity","volume":"205","author":"C Mu\u00f1oz-Fontela","year":"2008","journal-title":"J Exp Med"},{"key":"ppat.1013622.ref031","doi-asserted-by":"crossref","first-page":"101413","DOI":"10.1016\/j.coviro.2024.101413","article-title":"A comparative review of adenovirus A12 and C5 oncogenes","volume":"67","author":"LD Bertzbach","year":"2024","journal-title":"Curr Opin Virol"},{"issue":"6","key":"ppat.1013622.ref032","doi-asserted-by":"crossref","first-page":"642","DOI":"10.15252\/embr.201438638","article-title":"The Hippo signaling pathway in stem cell biology and cancer","volume":"15","author":"J-S Mo","year":"2014","journal-title":"EMBO Rep"},{"key":"ppat.1013622.ref033","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.3389\/fmicb.2019.03033","article-title":"The Hippo Pathway and Viral Infections","volume":"10","author":"Z Wang","year":"2020","journal-title":"Front Microbiol"},{"issue":"1","key":"ppat.1013622.ref034","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/cdd.2017.163","article-title":"p53 shades of Hippo","volume":"25","author":"N Furth","year":"2018","journal-title":"Cell Death Differ"},{"issue":"19","key":"ppat.1013622.ref035","doi-asserted-by":"crossref","first-page":"5530","DOI":"10.1111\/febs.15637","article-title":"The multifaceted role of TRAIL signaling in cancer and immunity","volume":"288","author":"L Cardoso Alves","year":"2021","journal-title":"FEBS J"},{"issue":"11","key":"ppat.1013622.ref036","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.3390\/cancers12113227","article-title":"Toll-Like Receptor 3 in Solid Cancer and Therapy Resistance","volume":"12","author":"XM Muresan","year":"2020","journal-title":"Cancers (Basel)"},{"key":"ppat.1013622.ref037","doi-asserted-by":"crossref","first-page":"1148389","DOI":"10.3389\/fmolb.2023.1148389","article-title":"The role of p53 in anti-tumor immunity and response to immunotherapy","volume":"10","author":"L Carlsen","year":"2023","journal-title":"Front Mol Biosci"},{"issue":"10","key":"ppat.1013622.ref038","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.3390\/pharmaceutics13101585","article-title":"The Revolving Door of Adenovirus Cell Entry: Not All Pathways Are Equal","volume":"13","author":"D Nesti\u0107","year":"2021","journal-title":"Pharmaceutics"},{"issue":"8","key":"ppat.1013622.ref039","doi-asserted-by":"crossref","first-page":"4432","DOI":"10.1128\/JVI.03387-12","article-title":"The repression domain of the E1B 55-kilodalton protein participates in countering interferon-induced inhibition of adenovirus replication","volume":"87","author":"JS Chahal","year":"2013","journal-title":"J Virol"},{"issue":"4","key":"ppat.1013622.ref040","doi-asserted-by":"crossref","first-page":"395","DOI":"10.5114\/ceji.2015.56960","article-title":"Inhibition of adenovirus multiplication by inosine pranobex and interferon \u03b1 in vitro","volume":"40","author":"A Majewska","year":"2015","journal-title":"Cent Eur J Immunol"},{"issue":"9","key":"ppat.1013622.ref041","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00250-18","article-title":"Adenovirus Infection of Human Enteroids Reveals Interferon Sensitivity and Preferential Infection of Goblet Cells","volume":"92","author":"MK Holly","year":"2018","journal-title":"J Virol"},{"issue":"6948","key":"ppat.1013622.ref042","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/nature01850","article-title":"Integration of interferon-alpha\/beta signalling to p53 responses in tumour suppression and antiviral defence","volume":"424","author":"A Takaoka","year":"2003","journal-title":"Nature"},{"issue":"18","key":"ppat.1013622.ref043","doi-asserted-by":"crossref","first-page":"2914","DOI":"10.1038\/sj.onc.1205459","article-title":"Identification of the interferon regulatory factor 5 gene (IRF-5) as a direct target for p53","volume":"21","author":"T Mori","year":"2002","journal-title":"Oncogene"},{"issue":"5","key":"ppat.1013622.ref044","doi-asserted-by":"crossref","first-page":"3172","DOI":"10.1074\/jbc.M114.619890","article-title":"p53 degradation by a coronavirus papain-like protease suppresses type I interferon signaling","volume":"290","author":"L Yuan","year":"2015","journal-title":"J Biol Chem"},{"issue":"23","key":"ppat.1013622.ref045","doi-asserted-by":"crossref","first-page":"12210","DOI":"10.1128\/JVI.01442-10","article-title":"Adenovirus E1B 55-kilodalton protein is a p53-SUMO1 E3 ligase that represses p53 and stimulates its nuclear export through interactions with promyelocytic leukemia nuclear bodies","volume":"84","author":"MA Pennella","year":"2010","journal-title":"J Virol"},{"issue":"11","key":"ppat.1013622.ref046","article-title":"Adenovirus E1B-55K controls SUMO-dependent degradation of antiviral cellular restriction factors","volume":"97","author":"W-H Ip","year":"2023","journal-title":"J Virol"},{"issue":"7","key":"ppat.1013622.ref047","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.tim.2021.12.011","article-title":"Mitochondria-mediated oxidative stress during viral infection","volume":"30","author":"J Foo","year":"2022","journal-title":"Trends Microbiol"},{"issue":"10","key":"ppat.1013622.ref048","first-page":"2552","article-title":"Adenovirus E1B proteins are required for accumulation of late viral mRNA and for effects on cellular mRNA translation and transport","volume":"5","author":"LE Babiss","year":"1985","journal-title":"Mol Cell Biol"},{"issue":"2","key":"ppat.1013622.ref049","first-page":"470","article-title":"The adenovirus E1B-55K transforming polypeptide modulates transport or cytoplasmic stabilization of viral and host cell mRNAs","volume":"6","author":"S Pilder","year":"1986","journal-title":"Mol Cell Biol"},{"issue":"19","key":"ppat.1013622.ref050","doi-asserted-by":"crossref","first-page":"9970","DOI":"10.1128\/JVI.01113-09","article-title":"The adenovirus E1B 55-kilodalton and E4 open reading frame 6 proteins limit phosphorylation of eIF2alpha during the late phase of infection","volume":"83","author":"ME Spurgeon","year":"2009","journal-title":"J Virol"},{"key":"ppat.1013622.ref051","doi-asserted-by":"crossref","first-page":"200239","DOI":"10.1016\/j.tvr.2022.200239","article-title":"Small DNA tumor viruses and human cancer: Preclinical models of virus infection and disease","volume":"14","author":"ME Spurgeon","year":"2022","journal-title":"Tumour Virus Res"},{"issue":"1","key":"ppat.1013622.ref052","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/wsbm.88","article-title":"The critical protein interactions and structures that elicit growth deregulation in cancer and viral replication","volume":"3","author":"HD Ou","year":"2011","journal-title":"Wiley Interdiscip Rev Syst Biol Med"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1013622","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013622","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T18:51:27Z","timestamp":1762455087000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013622"}},"subtitle":[],"editor":[{"given":"Corey","family":"Smith","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,11,3]]},"references-count":52,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1013622","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,3]]}}}