{"doi":"10.1101/2025.03.19.644084","title":"UFMylation of 14-3-3ε coordinates MAVS signaling complex assembly to promote antiviral innate immune induction","abstract":"Post-translational modifications are critical for regulating the RIG-I signaling pathway. Previously, we identified a role for the post-translation modification UFM1 (UFMylation) in promoting RIG-I signaling by stimulating the interaction between RIG-I and its membrane-targeting protein 14-3-3ε. Here, we identify UFMylation of 14-3-3ε as a novel regulatory mechanism promoting RIG-I signaling. We demonstrate that UFM1 conjugation to lysine residue K50 or K215 results in mono-UFMylation on 14-3-3ε and enhances its ability to promote RIG-I signaling. Importantly, we show that mutation of these residues (K50R/K215R) abolishes UFMylation and impairs induction of type I and III interferons without disrupting the interaction between 14-3-3ε and RIG-I. This suggests that UFMylation of 14-3-3ε likely stabilizes signaling events downstream of RIG-I activation to promote induction of interferon. Collectively, our work suggests that UFMylation-driven activation of 14-3-3ε facilitates innate immune signaling and highlights the broader role of UFMylation for antiviral defense and immune regulation. Importance: Post-translational modifications provide regulatory control of antiviral innate immune responses. Our study reveals that UFMylation of 14-3-3ε is a control point for RIG-I-mediated antiviral signaling. We demonstrate that conjugation of UFM1 to specific lysine residues on 14-3-3ε enhances downstream signaling events that facilitate interferon induction, but surprisingly it does not affect 14-3-3ε binding to RIG-I. By identifying the precise sites of UFMylation on 14-3-3ε and their functional consequences, we provide insights into the regulatory layers governing antiviral innate immunity. These findings complement emerging evidence that UFMylation serves as a versatile modulator across diverse immune pathways. Furthermore, our work highlights how protein chaperones like 14-3-3ε can be dynamically modified to orchestrate complex signaling cascades, suggesting potential therapeutic approaches for targeting dysregulated innate immunity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557436,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"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":547697,"name":"Moonhee Park","orcid":null,"position":1,"is_corresponding":false},{"id":1457649,"name":"Lauren Sar","orcid":null,"position":2,"is_corresponding":false},{"id":779370,"name":"Ryan Rodriguez","orcid":"0009-0005-0157-1627","position":3,"is_corresponding":false},{"id":1391651,"name":"Hannah M. Schmidt","orcid":"0000-0002-7980-4938","position":4,"is_corresponding":false},{"id":343903,"name":"Daltry L. Snider","orcid":"0000-0002-0563-3101","position":5,"is_corresponding":false},{"id":1457650,"name":"Gabriella Torres","orcid":null,"position":6,"is_corresponding":false},{"id":586971,"name":"K. Matthew Scaglione","orcid":"0000-0002-3858-9418","position":7,"is_corresponding":false},{"id":229072,"name":"Stacy M. Horner","orcid":"0000-0002-9351-7409","position":8,"is_corresponding":false},{"id":1310900,"name":"Isaura Vanessa Gutierrez","orcid":null,"position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:55:17.435961Z","pmid":"40166322","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":[]}