{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T09:08:42Z","timestamp":1789722522303,"version":"4.0.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011849","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000}}],"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T00:00:00Z","timestamp":1701820800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006692","name":"Universit\u00e0 degli Studi di Torino","doi-asserted-by":"publisher","award":["RILO2021"],"award-info":[{"award-number":["RILO2021"]}],"id":[{"id":"10.13039\/501100006692","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006692","name":"Universit\u00e0 degli Studi di Torino","doi-asserted-by":"publisher","award":["RILO2022"],"award-info":[{"award-number":["RILO2022"]}],"id":[{"id":"10.13039\/501100006692","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006692","name":"Universit\u00e0 degli Studi di Torino","doi-asserted-by":"publisher","award":["RILO2022"],"award-info":[{"award-number":["RILO2022"]}],"id":[{"id":"10.13039\/501100006692","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006692","name":"Universit\u00e0 degli Studi di Torino","doi-asserted-by":"publisher","award":["RILO2022"],"award-info":[{"award-number":["RILO2022"]}],"id":[{"id":"10.13039\/501100006692","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["2017ALPCM"],"award-info":[{"award-number":["2017ALPCM"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015954","name":"Fondazione Cassa di Risparmio di Vercelli","doi-asserted-by":"publisher","award":["RF2021.1745"],"award-info":[{"award-number":["RF2021.1745"]}],"id":[{"id":"10.13039\/100015954","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["INF-ACT PE00000007"],"award-info":[{"award-number":["INF-ACT PE00000007"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Herpes simplex virus 1 (HSV-1) is a neurotropic virus that remains latent in neuronal cell bodies but reactivates throughout an individual\u2019s life, causing severe adverse reactions, such as herpes simplex encephalitis (HSE). Recently, it has also been implicated in the etiology of Alzheimer\u2019s disease (AD). The absence of an effective vaccine and the emergence of numerous drug-resistant variants have called for the development of new antiviral agents that can tackle HSV-1 infection. Host-targeting antivirals (HTAs) have recently emerged as promising antiviral compounds that act on host-cell factors essential for viral replication. Here we show that a new class of HTAs targeting peptidylarginine deiminases (PADs), a family of calcium-dependent enzymes catalyzing protein citrullination, exhibits a marked inhibitory activity against HSV-1. Furthermore, we show that HSV-1 infection leads to enhanced protein citrullination through transcriptional activation of three PAD isoforms: PAD2, PAD3, and PAD4. Interestingly, PAD3-depletion by specific drugs or siRNAs dramatically inhibits HSV-1 replication. Finally, an analysis of the citrullinome reveals significant changes in the deimination levels of both cellular and viral proteins, with the interferon (IFN)-inducible proteins IFIT1 and IFIT2 being among the most heavily deiminated ones. As genetic depletion of IFIT1 and IFIT2 strongly enhances HSV-1 growth, we propose that viral-induced citrullination of IFIT1 and 2 is a highly efficient HSV-1 evasion mechanism from host antiviral resistance. Overall, our findings point to a crucial role of citrullination in subverting cellular responses to viral infection and demonstrate that PAD inhibitors efficiently suppress HSV-1 infection\n                    <jats:italic>in vitro<\/jats:italic>\n                    , which may provide the rationale for their repurposing as HSV-1 antiviral drugs.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011849","type":"journal-article","created":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T13:44:56Z","timestamp":1701870296000},"page":"e1011849","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Citrullination profile analysis reveals peptidylarginine deaminase 3 as an HSV-1 target to dampen the activity of candidate antiviral restriction factors"],"prefix":"10.1371","volume":"19","author":[{"given":"Selina","family":"Pasquero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Gugliesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Biolatti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Dell\u2019Oste","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Albano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greta","family":"Bajetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Griffante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Trifir\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Brugo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Raviola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Lacarbonara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Sudeshna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Barasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hafeez","family":"Haniff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santo","family":"Landolfo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3188-5783","authenticated-orcid":true,"given":"Marco","family":"De Andrea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,12,6]]},"reference":[{"key":"ppat.1011849.ref001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/bmjgh-2020-002388","article-title":"Herpes simplex virus type 1 in Europe: Systematic review, meta-analyses and meta-regressions","volume":"5","author":"W Yousuf","year":"2020","journal-title":"BMJ Global Health"},{"key":"ppat.1011849.ref002","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s12223-016-0482-7","article-title":"Herpesvirus: an underestimated 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Krishnan","year":"2021","journal-title":"Frontiers in Microbiology"},{"key":"ppat.1011849.ref006","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/v13071228","article-title":"Current drugs to treat infections with herpes simplex viruses-1 and -2","volume":"13","author":"LA Sadowski","year":"2021","journal-title":"Viruses"},{"key":"ppat.1011849.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fviro.2022.935933","article-title":"Viral-Host Dependency Factors as Therapeutic Targets to Overcome Antiviral Drug-Resistance: A Focus on Innate Immune Modulation","volume":"2","author":"R Badia","year":"2022","journal-title":"Frontiers in Virology"},{"key":"ppat.1011849.ref008","doi-asserted-by":"crossref","DOI":"10.1128\/mSystems.00388-21","article-title":"Target Discovery for Host-Directed Antiviral Therapies: Application of Proteomics Approaches","volume":"6","author":"M Cakir","year":"2021","journal-title":"mSystems"},{"key":"ppat.1011849.ref009","doi-asserted-by":"crossref","first-page":"700","DOI":"10.2174\/1389450116666150202160954","article-title":"Protein Arginine Deiminases and Associated Citrullination: Physiological Functions and Diseases Associated with Dysregulation","volume":"16","author":"E Witalisom","year":"2015","journal-title":"Curr Drug Targets"},{"key":"ppat.1011849.ref010","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1021\/acs.accounts.9b00024","article-title":"Protein Arginine Deiminases (PADs): Biochemistry and Chemical Biology of Protein Citrullination","volume":"52","author":"S Mondal","year":"2019","journal-title":"Accounts of Chemical Research"},{"key":"ppat.1011849.ref011","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.autrev.2015.01.013","article-title":"Citrullination and autoimmunity","volume":"14","author":"G Valesini","year":"2015","journal-title":"Autoimmunity 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Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection","volume":"11","author":"V Casanova","year":"2020","journal-title":"Frontiers in Immunology"},{"key":"ppat.1011849.ref028","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1038\/s41598-018-22058-6","article-title":"Antibodies to a strain-specific citrullinated Epstein-Barr virus peptide diagnoses rheumatoid arthritis","volume":"8","author":"NH Trier","year":"2018","journal-title":"Scientific Reports"},{"key":"ppat.1011849.ref029","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1365-2249.2011.04378.x","article-title":"Antibodies to a new viral citrullinated peptide, VCP2: fine specificity and correlation with anti-cyclic citrullinated peptide (CCP) and anti-VCP1 antibodies","volume":"164","author":"F Pratesi","year":"2011","journal-title":"Clinical & Experimental 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Identification of Multiple Structurally Distinct, Nonpeptidic Small Molecule Inhibitors of Protein Arginine Deiminase 3 Using a Substrate-Based Fragment Method. 2015.","DOI":"10.1021\/jacs.5b00095"},{"key":"ppat.1011849.ref036","doi-asserted-by":"crossref","first-page":"12910","DOI":"10.1074\/jbc.REV120.013930","article-title":"The molecular virology of coronaviruses","volume":"295","author":"E Hartenian","year":"2020","journal-title":"J Biol Chem"},{"key":"ppat.1011849.ref037","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2021.716250","article-title":"Applicability of Small-Molecule Inhibitors in the Study of Peptidyl Arginine Deiminase 2 (PAD2) and PAD4","volume":"12","author":"MT Mart\u00edn Monreal","year":"2021","journal-title":"Frontiers in Immunology"},{"key":"ppat.1011849.ref038","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2014.00094","article-title":"IFITs: Emerging roles as key anti-viral proteins","volume":"5","author":"GI Vladimer","year":"2014","journal-title":"Frontiers in Immunology"},{"key":"ppat.1011849.ref039","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1099\/jgv.0.001149","article-title":"Better together: The role of IFIT protein-protein interactions in the antiviral response","volume":"99","author":"H V. 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