{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T19:24:58Z","timestamp":1771356298218,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013955","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000}}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Viruses are recognized by host cell innate immunity through viral RNA\/DNA sensing by cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING). However, many viruses evade cGAS-STING signaling and antiviral IFN-\u03b2 response. Here, we show that natural killer (NK) cells counteract immune evasion of type I interferon response upon human cytomegalovirus (HCMV) infection. NK cells enhance IFN-\u03b2 response in virus-infected cells more efficiently than perforin-knockout and GrM-knockout NK cells. Mechanistically, GrM cleaves viral pp71 into two fragments, the first, like full-length pp71, still inhibits cGAS-STING-IFN-\u03b2 response but is rapidly degraded by the proteasome, and the second fragment that rather augments IFN-\u03b2 and outperforms full-length pp71 inhibition of STING. NK cells cannot enhance IFN-\u03b2 response in cells infected with HCMV that harbors a pp71 with a mutated GrM cleavage site. We conclude that NK cells use GrM to counteract cytomegaloviral innate immune evasion through pp71-mediated inhibition of cGAS-STING-IFN-\u03b2 innate immune response.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013955","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T18:45:32Z","timestamp":1770662732000},"page":"e1013955","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytotoxic lymphocytes counteract viral type I interferon immune evasion"],"prefix":"10.1371","volume":"22","author":[{"given":"Michael Y.","family":"Schakelaar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liling","family":"Shan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rianne G.","family":"Bouma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josefien W.","family":"Hommes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorine G. F.","family":"Sanders","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Meeldijk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura L.","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toine","family":"ten Broeke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert F.","family":"Kalejta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8526-4456","authenticated-orcid":true,"given":"Niels","family":"Bovenschen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"issue":"6","key":"ppat.1013955.ref001","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/nri819","article-title":"Cytotoxic T lymphocytes: all roads lead to death","volume":"2","author":"M Barry","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"ppat.1013955.ref002","first-page":"954602","article-title":"Cytotoxic CD4 T cells in antiviral immunity","volume":"2011","author":"NB Marshall","year":"2011","journal-title":"J Biomed Biotechnol"},{"issue":"2","key":"ppat.1013955.ref003","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nri.2015.9","article-title":"Natural killer cell memory in infection, inflammation and cancer","volume":"16","author":"A Cerwenka","year":"2016","journal-title":"Nat Rev Immunol"},{"issue":"2","key":"ppat.1013955.ref004","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41577-021-00558-3","article-title":"Natural killer cells in antiviral immunity","volume":"22","author":"NK Bj\u00f6rkstr\u00f6m","year":"2022","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"ppat.1013955.ref005","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1128\/JVI.79.1.661-667.2005","article-title":"Natural killer cells utilize both perforin and gamma interferon to regulate murine cytomegalovirus infection in the spleen and liver","volume":"79","author":"J Loh","year":"2005","journal-title":"J Virol"},{"issue":"3","key":"ppat.1013955.ref006","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1128\/CDLI.8.3.628-631.2001","article-title":"Gamma interferon expression in CD8(+) T cells is a marker for circulating cytotoxic T lymphocytes that recognize an HLA A2-restricted epitope of human cytomegalovirus phosphoprotein pp65","volume":"8","author":"SA Ghanekar","year":"2001","journal-title":"Clin Diagn Lab Immunol"},{"key":"ppat.1013955.ref007","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1146\/annurev.immunol.26.021607.090404","article-title":"Death by a thousand cuts: granzyme pathways of programmed cell death","volume":"26","author":"D Chowdhury","year":"2008","journal-title":"Annu Rev Immunol"},{"issue":"1","key":"ppat.1013955.ref008","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/j.0105-2896.2010.00889.x","article-title":"Orphan granzymes find a home","volume":"235","author":"N Bovenschen","year":"2010","journal-title":"Immunol Rev"},{"issue":"3","key":"ppat.1013955.ref009","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/cdd.2013.189","article-title":"Granzyme M: behind enemy lines","volume":"21","author":"SAH de Poot","year":"2014","journal-title":"Cell Death Differ"},{"issue":"12","key":"ppat.1013955.ref010","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2001-2-12-reviews3014","article-title":"Granzymes: a family of lymphocyte granule serine proteases","volume":"2","author":"JA Trapani","year":"2001","journal-title":"Genome Biol"},{"issue":"5","key":"ppat.1013955.ref011","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1038\/cdd.2011.178","article-title":"Granzyme K inhibits replication of influenza virus through cleaving the nuclear transport complex importin \u03b11\/\u03b2 dimer of infected host cells","volume":"19","author":"C Zhong","year":"2012","journal-title":"Cell Death Differ"},{"issue":"9","key":"ppat.1013955.ref012","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":"K-P Hopfner","year":"2020","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ppat.1013955.ref013","doi-asserted-by":"crossref","first-page":"113831","DOI":"10.1016\/j.bcp.2020.113831","article-title":"Targeting of the cGAS-STING system by DNA viruses","volume":"174","author":"T Phelan","year":"2020","journal-title":"Biochem Pharmacol"},{"issue":"2","key":"ppat.1013955.ref014","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":"Z Ma","year":"2016","journal-title":"Cell Host Microbe"},{"issue":"3","key":"ppat.1013955.ref015","doi-asserted-by":"crossref","DOI":"10.1002\/rmv.2034","article-title":"Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis","volume":"29","author":"M Zuhair","year":"2019","journal-title":"Rev Med Virol"},{"key":"ppat.1013955.ref016","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":"T Crough","year":"2009","journal-title":"Clin Microbiol Rev"},{"issue":"3","key":"ppat.1013955.ref017","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.jcv.2007.11.014","article-title":"Human cytomegalovirus: Latency and reactivation in the myeloid lineage","volume":"41","author":"J Sinclair","year":"2008","journal-title":"J Clin Virol"},{"issue":"2","key":"ppat.1013955.ref018","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":"MR Wills","year":"2015","journal-title":"Cell Mol Immunol"},{"issue":"2","key":"ppat.1013955.ref019","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/path.4437","article-title":"The pathogenesis of human cytomegalovirus","volume":"235","author":"P Griffiths","year":"2015","journal-title":"J Pathol"},{"issue":"6","key":"ppat.1013955.ref020","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1016\/j.tranon.2018.08.003","article-title":"Impact of Human Cytomegalovirus Infection and its Immune Response on Survival of Patients with Ovarian Cancer","volume":"11","author":"AF R\u00e5destad","year":"2018","journal-title":"Transl Oncol"},{"issue":"11","key":"ppat.1013955.ref021","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1002\/jmv.23820","article-title":"High prevalence of HCMV and viral load in tumor tissues and peripheral blood of glioblastoma multiforme patients","volume":"86","author":"CJ dos Santos","year":"2014","journal-title":"J Med Virol"},{"key":"ppat.1013955.ref022","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1128\/MMBR.00040-07","article-title":"Tegument Proteins of Human Cytomegalovirus","volume":"72","author":"RF Kalejta","year":"2008","journal-title":"Microbiol Mol Biol Rev"},{"key":"ppat.1013955.ref023","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1743-422X-9-22","article-title":"Human cytomegalovirus tegument proteins (pp65, pp71, pp150, pp28)","volume":"9","author":"JP Tomtishen","year":"2012","journal-title":"Virol J"},{"issue":"26","key":"ppat.1013955.ref024","doi-asserted-by":"crossref","first-page":"14506","DOI":"10.1073\/pnas.97.26.14506","article-title":"UL82 virion protein activates expression of immediate early viral genes in human cytomegalovirus-infected cells","volume":"97","author":"WA Bresnahan","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"9","key":"ppat.1013955.ref025","doi-asserted-by":"crossref","first-page":"855","DOI":"10.2217\/fvl.12.86","article-title":"Tale of a tegument transactivator: the past, present and future of human CMV pp71","volume":"7","author":"RR Penkert","year":"2012","journal-title":"Future Virol"},{"key":"ppat.1013955.ref026","doi-asserted-by":"crossref","first-page":"95","DOI":"10.3389\/fcimb.2020.00095","article-title":"Expanding the Known Functional Repertoire of the Human Cytomegalovirus pp71 Protein","volume":"10","author":"RF Kalejta","year":"2020","journal-title":"Front Cell Infect Microbiol"},{"issue":"12","key":"ppat.1013955.ref027","doi-asserted-by":"crossref","first-page":"7605","DOI":"10.4049\/jimmunol.1001503","article-title":"Noncytotoxic inhibition of cytomegalovirus replication through NK cell protease granzyme M-mediated cleavage of viral phosphoprotein 71","volume":"185","author":"R van Domselaar","year":"2010","journal-title":"J Immunol"},{"issue":"6","key":"ppat.1013955.ref028","doi-asserted-by":"crossref","first-page":"3873","DOI":"10.1128\/JVI.79.6.3873-3877.2005","article-title":"Human cytomegalovirus immediate-early 2 gene expression blocks virus-induced beta interferon production","volume":"79","author":"RT Taylor","year":"2005","journal-title":"J Virol"},{"issue":"4","key":"ppat.1013955.ref029","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1005546","article-title":"cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells","volume":"12","author":"J Paijo","year":"2016","journal-title":"PLoS Pathog"},{"issue":"2","key":"ppat.1013955.ref030","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.chom.2017.01.001","article-title":"Human Cytomegalovirus Tegument Protein UL82 Inhibits STING-Mediated Signaling to Evade Antiviral Immunity","volume":"21","author":"Y-Z Fu","year":"2017","journal-title":"Cell Host Microbe"},{"issue":"11","key":"ppat.1013955.ref031","doi-asserted-by":"crossref","first-page":"7568","DOI":"10.4049\/jimmunol.175.11.7568","article-title":"Human NK cells inhibit cytomegalovirus replication through a noncytolytic mechanism involving lymphotoxin-dependent induction of IFN-beta","volume":"175","author":"A-C Iversen","year":"2005","journal-title":"J Immunol"},{"key":"ppat.1013955.ref032","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/S1074-7613(01)00222-9","article-title":"Lymphotoxins and cytomegalovirus cooperatively induce interferon-\u03b2, establishing host-virus d\u00e9tente","volume":"15","author":"CA Benedict","year":"2001","journal-title":"Immunity"},{"key":"ppat.1013955.ref033","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.02214","article-title":"HCMV-encoded NK modulators: lessons from in vitro and in vivo genetic variation","volume":"9","author":"M Patel","year":"2018","journal-title":"Front Immunol"},{"issue":"3","key":"ppat.1013955.ref034","doi-asserted-by":"crossref","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":"ER Albright","year":"2023","journal-title":"J Virol"},{"issue":"5","key":"ppat.1013955.ref035","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1128\/JVI.03489-14","article-title":"Natural killer cells can inhibit the transmission of human cytomegalovirus in cell culture by using mechanisms from innate and adaptive immune responses","volume":"89","author":"Z Wu","year":"2015","journal-title":"J Virol"},{"issue":"2","key":"ppat.1013955.ref036","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.smim.2014.02.001","article-title":"Human NK cell response to pathogens","volume":"26","author":"M Della Chiesa","year":"2014","journal-title":"Semin Immunol"},{"key":"ppat.1013955.ref037","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev.immunol.17.1.189","article-title":"Natural killer cells in antiviral defense: function and regulation by innate cytokines","volume":"17","author":"CA Biron","year":"1999","journal-title":"Annu Rev Immunol"},{"issue":"9","key":"ppat.1013955.ref038","doi-asserted-by":"crossref","first-page":"249","DOI":"10.3390\/v9090249","article-title":"Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus","volume":"9","author":"W Brune","year":"2017","journal-title":"Viruses"},{"key":"ppat.1013955.ref039","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.immuni.2016.01.010","article-title":"In vivo killing capacity of cytotoxic T cells is limited and involves dynamic interactions and T cell cooperativity","volume":"44","author":"S Halle","year":"2016","journal-title":"Immunity"},{"issue":"6","key":"ppat.1013955.ref040","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01774-17","article-title":"Human Cytomegalovirus Tegument Protein pp65 (pUL83) Dampens Type I Interferon Production by Inactivating the DNA Sensor cGAS without Affecting STING","volume":"92","author":"M Biolatti","year":"2018","journal-title":"J Virol"},{"issue":"1","key":"ppat.1013955.ref041","article-title":"Human Cytomegalovirus Protein UL31 Inhibits DNA Sensing of cGAS to Mediate Immune Evasion","volume":"24","author":"Z-F Huang","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ppat.1013955.ref042","article-title":"Human Cytomegalovirus IE2 86 kDa Protein Induces STING Degradation and Inhibits cGAMP-Mediated IFN-\u03b2 Induction","volume":"8","author":"J-E Kim","year":"2017","journal-title":"Front Microbiol"},{"key":"ppat.1013955.ref043","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.02267-21","article-title":"Human cytomegalovirus UL138 protein inhibits the STING pathway and reduces interferon beta mRNA accumulation during lytic and latent infections","volume":"12","author":"ER Albright","year":"2021","journal-title":"mBio"},{"issue":"1","key":"ppat.1013955.ref044","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/s41392-021-00515-5","article-title":"Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins","volume":"6","author":"Y Rui","year":"2021","journal-title":"Signal Transduct Target Ther"},{"issue":"4","key":"ppat.1013955.ref045","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1006976","article-title":"STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice","volume":"14","author":"MK Skouboe","year":"2018","journal-title":"PLoS Pathog"},{"issue":"4","key":"ppat.1013955.ref046","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1008426","article-title":"Killer cell proteases can target viral immediate-early proteins to control human cytomegalovirus infection in a noncytotoxic manner","volume":"16","author":"L Shan","year":"2020","journal-title":"PLoS Pathog"},{"issue":"7","key":"ppat.1013955.ref047","doi-asserted-by":"crossref","first-page":"3109","DOI":"10.1128\/JVI.02124-06","article-title":"Human cytomegalovirus UL38 protein blocks apoptosis","volume":"81","author":"S Terhune","year":"2007","journal-title":"J Virol"},{"issue":"2","key":"ppat.1013955.ref048","doi-asserted-by":"crossref","first-page":"191","DOI":"10.2144\/000112096","article-title":"Two-step red-mediated recombination for versatile high-efficiency markerless DNA manipulation in Escherichia coli","volume":"40","author":"BK Tischer","year":"2006","journal-title":"Biotechniques"},{"key":"ppat.1013955.ref049","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.virol.2013.10.011","article-title":"Insertion of myeloid-active elements into the human cytomegalovirus major immediate early promoter is not sufficient to drive its activation upon infection of undifferentiated myeloid cells","volume":"448","author":"Q Qin","year":"2014","journal-title":"Virology"},{"issue":"5","key":"ppat.1013955.ref050","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1006382","article-title":"The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-\u03baB mediated transcription","volume":"13","author":"B Chan","year":"2017","journal-title":"PLoS Pathog"},{"issue":"3","key":"ppat.1013955.ref051","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/cdd.2012.132","article-title":"Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication","volume":"20","author":"R van Domselaar","year":"2013","journal-title":"Cell Death Differ"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1013955","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013955","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T18:53:09Z","timestamp":1771354389000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013955"}},"subtitle":[],"editor":[{"given":"Wolfram","family":"Brune","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,2,9]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1013955","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,9]]}}}