{"doi":"10.1126/sciimmunol.abq4531","title":"<i>GTF3A</i> mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand <i>RNA5SP141</i>","abstract":"Herpes simplex virus 1 (HSV-1) infects several billion people worldwide and can cause life-threatening herpes simplex encephalitis (HSE) in some patients. Monogenic defects in components of the type I interferon system have been identified in patients with HSE, emphasizing the role of inborn errors of immunity underlying HSE pathogenesis. Here, we identify compound heterozygous loss-of-function mutations in the gene GTF3A encoding for transcription factor IIIA (TFIIIA), a component of the RNA polymerase III complex, in a patient with common variable immunodeficiency and HSE. Patient fibroblasts and GTF3A gene–edited cells displayed impaired HSV-1–induced innate immune responses and enhanced HSV-1 replication. Chromatin immunoprecipitation sequencing analysis identified the 5 S ribosomal RNA pseudogene 141 ( RNA5SP141 ), an endogenous ligand of the RNA sensor RIG-I, as a transcriptional target of TFIIIA. GTF3A mutant cells exhibited diminished RNA5SP141 expression and abrogated RIG-I activation upon HSV-1 infection. Our work unveils a crucial role for TFIIIA in transcriptional regulation of a cellular RIG-I agonist and shows that GTF3A genetic defects lead to impaired cell-intrinsic anti–HSV-1 responses and can predispose to HSE.","journal":"Science Immunology","year":2022,"id":242719,"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":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":570830,"name":"Santoshi Muppala","orcid":"0000-0001-7830-9591","position":1,"is_corresponding":false},{"id":484708,"name":"Dhiraj Acharya","orcid":"0000-0003-1929-3870","position":2,"is_corresponding":false},{"id":873847,"name":"Josephine Nemegeer","orcid":"0000-0003-1688-8924","position":3,"is_corresponding":false},{"id":874454,"name":"Delfien Bogaert","orcid":null,"position":4,"is_corresponding":false},{"id":552405,"name":"Jung‐Hyun Lee","orcid":"0000-0003-1913-0027","position":5,"is_corresponding":false},{"id":873848,"name":"Katrien Staes","orcid":"0009-0004-2343-8686","position":6,"is_corresponding":false},{"id":873849,"name":"Veronique Debacker","orcid":"0000-0002-6525-9422","position":7,"is_corresponding":false},{"id":80061,"name":"Pieter De Bleser","orcid":"0000-0003-4762-8770","position":8,"is_corresponding":false},{"id":56983,"name":"Marieke De Bruyne","orcid":"0000-0001-6636-5537","position":9,"is_corresponding":false},{"id":832196,"name":"Elfride De Baere","orcid":"0000-0002-5609-6895","position":10,"is_corresponding":false},{"id":134874,"name":"Michiel van Gent","orcid":"0000-0003-3798-5360","position":11,"is_corresponding":false},{"id":552404,"name":"Guanqun Liu","orcid":"0000-0003-2520-7625","position":12,"is_corresponding":false},{"id":80095,"name":"Bart N. Lambrecht","orcid":"0000-0003-4376-6834","position":13,"is_corresponding":false},{"id":274465,"name":"Jens Staal","orcid":"0000-0003-2664-3357","position":14,"is_corresponding":false},{"id":424230,"name":"Tessa Kerre","orcid":"0000-0003-2114-2844","position":15,"is_corresponding":false},{"id":274486,"name":"Rudi Beyaert","orcid":"0000-0002-5704-582X","position":16,"is_corresponding":false},{"id":873850,"name":"Jonathan Maelfait","orcid":"0000-0002-1476-0583","position":17,"is_corresponding":false},{"id":274460,"name":"Simon J. Tavernier","orcid":"0000-0003-2514-5655","position":18,"is_corresponding":false},{"id":105617,"name":"Michaela U. Gack","orcid":"0000-0002-2163-2598","position":19,"is_corresponding":false},{"id":104186,"name":"Filomeen Haerynck","orcid":"0000-0001-9161-7361","position":20,"is_corresponding":false},{"id":424220,"name":"Leslie Naesens","orcid":"0000-0003-1715-0665","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T00:23:10.218426Z","pmid":"36399538","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":[]}