{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T19:56:40Z","timestamp":1788897400618,"version":"build-2803163510"},"posted":{"date-parts":[[2026,6,12]]},"group-title":"Immunology","reference-count":76,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["CRI14458"],"award-info":[{"award-number":["CRI14458"]}],"id":[{"id":"https:\/\/ror.org\/02f3xk561","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,11]]},"abstract":"<jats:p>\n                  Animal and bacterial cells defend against viral infection by rapidly activating antiviral restriction factors. In human cells, antiviral immunity is initiated by interferon signaling that results in expression of hundreds of interferon-stimulated genes (ISGs)\n                  <jats:sup>1,2,3,4,5,6<\/jats:sup>\n                  . Complex regulatory networks and co-evolution of viral evasion strategies complicate analysis of immune proteins under native conditions and the function of most individual ISGs remains unknown\n                  <jats:sup>7,8,9,10,11,12<\/jats:sup>\n                  . Here we discover that heterologous expression of ISGs in bacteria is sufficient to protect against infection by diverse bacteriophages demonstrating properties of antiviral restriction preserved across billions of years of viral evolution. A screen of 306 human ISGs against 11\n                  <jats:italic>E. coli<\/jats:italic>\n                  phages reveals that ISGs can restrict phage replication with potency equal to endogenous bacterial defense systems. We select for phage mutants that escape ISG restriction and identify the phage DNA primase-helicase complex as a target of human SPSB1. A 2.0 \u00c5 crystal structure of the SPSB1\u2013primase complex uncovers a recognition mechanism of foreign DxNxN protein motifs found in many animal and bacterial viral replication proteins. We show that SPSB1 in human cells recognizes and induces degradation of protein targets containing this motif from norovirus and poxvirus pathogens. Our results establish a cross-kingdom approach to studying immune function and reveal that human ISGs target features of viral replication common across kingdoms of life.\n                <\/jats:p>","DOI":"10.64898\/2026.06.11.731453","type":"posted-content","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T20:40:11Z","timestamp":1781296811000},"source":"Crossref","is-referenced-by-count":3,"title":["Human interferon stimulated genes target ancient features of animal and bacterial viral replication"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3303-9619","authenticated-orcid":false,"given":"Samantha G.","family":"Fernandez","sequence":"first","affiliation":[{"name":"Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill E.","family":"Hutchinson","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel M.J.","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonomi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne A.","family":"Roffler","sequence":"additional","affiliation":[{"name":"Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3627-2553","authenticated-orcid":false,"given":"Aaron G.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Kranzusch","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA"},{"name":"Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061607400923000_2026.06.11.731453v1.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.76.4.1824"},{"key":"2026061607400923000_2026.06.11.731453v1.2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.69.6.912"},{"key":"2026061607400923000_2026.06.11.731453v1.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.8009221"},{"key":"2026061607400923000_2026.06.11.731453v1.4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120231"},{"key":"2026061607400923000_2026.06.11.731453v1.5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2004086"},{"key":"2026061607400923000_2026.06.11.731453v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2022.101202"},{"key":"2026061607400923000_2026.06.11.731453v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nature09907"},{"key":"2026061607400923000_2026.06.11.731453v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/nature12862"},{"key":"2026061607400923000_2026.06.11.731453v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.07.012"},{"key":"2026061607400923000_2026.06.11.731453v1.10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009220"},{"key":"2026061607400923000_2026.06.11.731453v1.11","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1146\/annurev-virology-092818-015756","article-title":"Interferon-Stimulated Genes: What Do They All Do?","volume":"6","year":"2019","journal-title":"Annu Rev Virol"},{"key":"2026061607400923000_2026.06.11.731453v1.12","doi-asserted-by":"crossref","first-page":"4206","DOI":"10.1038\/s41467-026-72732-x","article-title":"The ISG Atlas: a loss-of-function analysis characterizes antiviral properties of interferon stimulated genes","volume":"17","year":"2026","journal-title":"Nat. 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