{"doi":"10.1128/jvi.01288-25","title":"GCN2 enhances host survival and drives eIF2α phosphorylation during mouse adenovirus type 1 infection","abstract":"ABSTRACT 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 2α (eIF2α) 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 Eif2ak4 tm1.2Dron mice (designated here Gcn2 −/ − mice) had lower survival than wild-type (WT) mice, but results indicated that this was not due to increased viral replication. Both Gcn2 −/ − and WT mice developed multifocal brain parenchymal microhemorrhages during infection. While Gcn2 −/ − animals had more lesions, their higher mortality is likely not due to the microhemorrhages alone. Cytokine RNA and protein assays of WT and Gcn2 −/ − mice only showed a difference for IL- β levels, which were higher in Gcn2 −/ − mice. Our results also indicate that of the two eIF2α kinases, PKR and GCN2, GCN2 is the primary inducer of phosphorylated-eIF2α during MAV-1 infection. GCN2 is thus antiviral and contributes to the host response to MAV-1 infection. IMPORTANCE 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 eIf2α 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 eIf2α phosphorylation.","journal":"Journal of Virology","year":2025,"id":575730,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1323318,"name":"David F. Edwards","orcid":"0009-0003-4781-0270","position":1,"is_corresponding":false},{"id":1483960,"name":"Rosario Labastida","orcid":"0009-0001-7366-1729","position":2,"is_corresponding":false},{"id":965023,"name":"Danielle E. Goodman","orcid":"0000-0003-3033-9147","position":3,"is_corresponding":false},{"id":1323319,"name":"Estela A. Pereira","orcid":"0009-0001-5281-4036","position":4,"is_corresponding":false},{"id":251568,"name":"Oded Foreman","orcid":"0000-0001-8197-3186","position":5,"is_corresponding":false},{"id":965025,"name":"Katherine R. Spindler","orcid":"0000-0002-9829-6051","position":6,"is_corresponding":false},{"id":1323320,"name":"Luíza Antunes de Castro-Jorge","orcid":"0000-0002-1595-3037","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:52.712371Z","pmid":"40990510","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}