{"doi":"10.1016/j.jbc.2023.104925","title":"SAMHD1 impairs type I interferon induction through the MAVS, IKKε, and IRF7 signaling axis during viral infection","abstract":"Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) restricts human immunodeficiency virus type 1 (HIV-1) infection by reducing the intracellular dNTP pool. We have shown that SAMHD1 suppresses nuclear factor kappa-B activation and type I interferon (IFN-I) induction by viral infection and inflammatory stimuli. However, the mechanism by which SAMHD1 inhibits IFN-I remains unclear. Here, we show that SAMHD1 inhibits IFN-I activation induced by the mitochondrial antiviral-signaling protein (MAVS). SAMHD1 interacted with MAVS and suppressed MAVS aggregation in response to Sendai virus infection in human monocytic THP-1 cells. This resulted in increased phosphorylation of TANK binding kinase 1 (TBK1), inhibitor of nuclear factor kappa-B kinase epsilon (IKKε), and IFN regulatory factor 3 (IRF3). SAMHD1 suppressed IFN-I activation induced by IKKε and prevented IRF7 binding to the kinase domain of IKKε. We found that SAMHD1 interaction with the inhibitory domain (ID) of IRF7 (IRF7-ID) was necessary and sufficient for SAMHD1 suppression of IRF7-mediated IFN-I activation in HEK293T cells. Computational docking and molecular dynamics simulations revealed possible binding sites between IRF7-ID and full-length SAMHD1. Individual substitution of F411, E416, or V460 in IRF7-ID significantly reduced IRF7 transactivation activity and SAMHD1 binding. Furthermore, we investigated the role of SAMHD1 inhibition of IRF7-mediated IFN-I induction during HIV-1 infection. We found that THP-1 cells lacking IRF7 expression had reduced HIV-1 infection and viral transcription compared to control cells, indicating a positive role of IRF7 in HIV-1 infection. Our findings suggest that SAMHD1 suppresses IFN-I induction through the MAVS, IKKε, and IRF7 signaling axis.","journal":"Journal of Biological Chemistry","year":2023,"id":344526,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":642194,"name":"Levent Sari","orcid":"0000-0003-4622-1864","position":1,"is_corresponding":false},{"id":294325,"name":"Michael P. Cahill","orcid":"0000-0002-5474-9311","position":2,"is_corresponding":false},{"id":1079552,"name":"Hua Yang","orcid":"0000-0002-7248-9410","position":3,"is_corresponding":false},{"id":471425,"name":"Stacia Phillips","orcid":"0000-0002-2801-459X","position":4,"is_corresponding":false},{"id":759855,"name":"Nicholas Martinez","orcid":"0000-0003-3026-8887","position":5,"is_corresponding":false},{"id":241036,"name":"Adam D. Kenney","orcid":"0000-0002-9110-1178","position":6,"is_corresponding":false},{"id":241044,"name":"Jacob S. Yount","orcid":"0000-0002-6128-4575","position":7,"is_corresponding":false},{"id":246111,"name":"Yong Xiong","orcid":"0000-0001-9625-9313","position":8,"is_corresponding":false},{"id":444015,"name":"Milo M. Lin","orcid":"0000-0001-8680-2685","position":9,"is_corresponding":false},{"id":576943,"name":"Li Wu","orcid":"0000-0002-5468-2487","position":10,"is_corresponding":false},{"id":576941,"name":"Constanza E. Espada","orcid":"0000-0001-7487-5254","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T01:11:30.951510Z","pmid":"37328105","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":[]}