{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:06:39Z","timestamp":1785420399010,"version":"3.56.0"},"reference-count":65,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI133935"],"award-info":[{"award-number":["R01AI133935"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008455","name":"University of Michigan Medical School","doi-asserted-by":"publisher","award":["U081355"],"award-info":[{"award-number":["U081355"]}],"id":[{"id":"10.13039\/100008455","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2025,10,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The integrated stress response (ISR) is a cellular signaling pathway that reduces protein synthesis in the face of cellular stress, including viral infection. Two eukaryotic initiation factor 2\u03b1 (eIF2\u03b1) kinases, protein kinase R (PKR) and general control nonderepressible 2 (GCN2), are commonly activated during viral infections. Mouse adenovirus type 1 (MAV-1) infection leads to a steep reduction of PKR levels by proteasomal degradation. We assayed whether GCN2, a sensor of amino acid starvation and UV damage, plays a role in the ISR to MAV-1 infection. There was more phosphorylated GCN2 in MAV-1-infected cells, and its activation was dependent on virus replication since UV-inactivated virus was not able to increase the phosphorylation of GCN2. Infected\n                      <jats:italic toggle=\"yes\">\n                        Eif2ak4\n                        <jats:sup>tm1.2Dron<\/jats:sup>\n                      <\/jats:italic>\n                      mice (designated here\n                      <jats:italic toggle=\"yes\">\n                        Gcn2\n                        <jats:sup>\u2212\/<\/jats:sup>\n                      <\/jats:italic>\n                      <jats:sup>\u2212<\/jats:sup>\n                      mice) had lower survival than wild-type (WT) mice, but results indicated that this was not due to increased viral replication. Both\n                      <jats:italic toggle=\"yes\">\n                        Gcn2\n                        <jats:sup>\u2212\/<\/jats:sup>\n                      <\/jats:italic>\n                      <jats:sup>\u2212<\/jats:sup>\n                      and WT mice developed multifocal brain parenchymal microhemorrhages during infection. While\n                      <jats:italic toggle=\"yes\">\n                        Gcn2\n                        <jats:sup>\u2212\/<\/jats:sup>\n                      <\/jats:italic>\n                      <jats:sup>\u2212<\/jats:sup>\n                      animals had more lesions, their higher mortality is likely not due to the microhemorrhages alone. Cytokine RNA and protein assays of WT and\n                      <jats:italic toggle=\"yes\">\n                        Gcn2\n                        <jats:sup>\u2212\/<\/jats:sup>\n                      <\/jats:italic>\n                      <jats:sup>\u2212<\/jats:sup>\n                      mice only showed a difference for IL- \u03b2 levels, which were higher in\n                      <jats:italic toggle=\"yes\">\n                        Gcn2\n                        <jats:sup>\u2212\/<\/jats:sup>\n                      <\/jats:italic>\n                      <jats:sup>\u2212<\/jats:sup>\n                      mice. Our results also indicate that of the two eIF2\u03b1 kinases, PKR and GCN2, GCN2 is the primary inducer of phosphorylated-eIF2\u03b1 during MAV-1 infection. GCN2 is thus antiviral and contributes to the host response to MAV-1 infection.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Cells often respond to viral infection by activation of the host protein kinase R (PKR), part of the integrated stress response (ISR). We show that a second host protein kinase, general control nonderepressible 2 (GCN2), is activated by phosphorylation in response to mouse adenovirus type 1 (MAV-1) infection. Our results indicate GCN2 is antiviral: without it, the mortality in MAV-1-infected mouse is higher. Furthermore, the data show that GCN2, rather than PKR, is the main inducer of eIf2\u03b1 phosphorylation (and thus the ISR) upon MAV-1 infection. This is consistent with PKR exerting antiviral effects in MAV-1 infections through a pathway independent of eIf2\u03b1 phosphorylation.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01288-25","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T13:00:20Z","timestamp":1758718820000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["GCN2 enhances host survival and drives eIF2\u03b1 phosphorylation during mouse adenovirus type 1 infection"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1595-3037","authenticated-orcid":true,"given":"Luiza A.","family":"Castro Jorge","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Michigan","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4781-0270","authenticated-orcid":true,"suffix":"III","given":"Daniel F.","family":"Edwards","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Michigan","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7366-1729","authenticated-orcid":true,"given":"Rosario","family":"Labastida","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Michigan","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3033-9147","authenticated-orcid":true,"given":"Danielle E.","family":"Goodman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Michigan","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5281-4036","authenticated-orcid":true,"given":"Estela A.","family":"Pereira","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Michigan","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8197-3186","authenticated-orcid":true,"given":"Oded","family":"Foreman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Genentech Inc.","place":["South San Francisco, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9829-6051","authenticated-orcid":true,"given":"Katherine R.","family":"Spindler","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Michigan","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642195"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1097-2765(03)00105-9"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801400200"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1089\/jir.1993.13.241"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/16729"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.12.4579"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0960-9822(02)01037-0"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806735200"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1995.9937"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1993.1292"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00254-10"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)31463-7"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02199-05"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1999.1583"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.11.8620-8626.1998"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.74.23.11215-11221.2000"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(86)90383-1"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.63.5.2244-2251.1989"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02148-08"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000287"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02506-12"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2017.06.023"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00284"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1101\/584680"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02063-21"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2023.109660"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.69.12.7674-7681.1995"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.24.12039-12046.2001"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-012369454-6\/50030-3"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4800(68)90053-1"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02077-14"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01545-24"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05660-11"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2024.168594"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601073"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0047272"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1272-x"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae006"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1246829"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.02.031"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17186"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.3390\/metabo13101064"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24054285"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mex.2017.10.008"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2009.06.004"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2005.03.004"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1998.9180"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.2.1219-1223.1998"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.69.12.8084-8088.1995"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00954-09"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001887"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2005.08.006"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2103280118"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.3389\/fsurg.2025.1559195"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2013.12.012"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.012485299"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008250"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(02)00642-6"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(91)90030-F"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1385\/1-59745-166-5:41"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2009.05.025"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2008.07.031"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.23.12888-12900.2004"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-2079-3_11"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02106-16"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/jvi.01288-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/jvi.01288-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T13:15:48Z","timestamp":1761225348000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/jvi.01288-25"}},"subtitle":[],"editor":[{"given":"Karl","family":"M\u00fcnger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,10,23]]},"references-count":65,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10,23]]}},"alternative-id":["10.1128\/jvi.01288-25"],"URL":"https:\/\/doi.org\/10.1128\/jvi.01288-25","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,23]]},"assertion":[{"value":"2025-07-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01288-25"}}