{"doi":"10.1128/spectrum.03124-23","title":"miR-26a exerts broad-spectrum antiviral effects via the enhancement of RIG-I-mediated type I interferon response by targeting USP15","abstract":"ABSTRACT Host innate immunity is an important defense line against virus infection and is precisely regulated by various factors. Studying the mechanism of virus-host interaction is essential to developing novel antivirals. Being one of the key host natural antiviral responses, host small non-coding RNAs (miRNAs) possess promising antiviral potential worthy of study. Herein, we found that miR-26a exerted broad-spectrum antiviral effect against multiple viruses, e.g., Hepatitis E virus, Vesicular Stomatitis Virus, and Sendai Virus. Mechanistically, miR-26a specifically targets 3′UTR of mRNA to inhibit USP15 expression. USP15 interacted directly with RIG-I to deubiquitinate K63-linked RIG-I, thus negatively regulating type I interferon (IFN) signaling. Consequently, miR-26a, by downregulating USP15, promotes K63 ubiquitination of RIG-I to enhance type I IFN responses, resulting in an active antiviral state against virus infection. Intriguingly, the activation of type I IFN responses could suppress miR-26a expression, serving as an intrinsic negative feedback loop to avoid dysregulated signal activation. Hence, the broad-spectrum antiviral effects of miR-26a and its mode-of-action enriched the interaction networks between miRNAs and innate immunity, providing insights for the development of broad-spectrum antivirals against viral infection. IMPORTANCE miR-26a serves as a potent positive regulator of type I interferon (IFN) responses. By inhibiting USP15 expression, miR-26a promotes RIG-I K63-ubiquitination to enhance type I IFN responses, resulting in an active antiviral state against viruses. Being an intricate regulatory network, the activation of type I IFN responses could in turn suppress miR-26a expression to avoid the disordered activation that might result in the so-called “type I interferonopathy.” The knowledge gained would be essential for the development of novel antiviral strategies against viral infection.","journal":"Microbiology Spectrum","year":2023,"id":366456,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"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":1122675,"name":"Chunyang Li","orcid":"0000-0002-5798-2274","position":1,"is_corresponding":false},{"id":1123133,"name":"Yao Hou","orcid":null,"position":2,"is_corresponding":false},{"id":1122676,"name":"Dan Liu","orcid":"0000-0001-8789-0218","position":3,"is_corresponding":false},{"id":1122677,"name":"Qiudi Li","orcid":"0009-0003-5180-9053","position":4,"is_corresponding":false},{"id":1122678,"name":"Zijie Wang","orcid":"0000-0003-3831-3654","position":5,"is_corresponding":false},{"id":1122679,"name":"Renxian Tang","orcid":"0000-0002-4205-1071","position":6,"is_corresponding":false},{"id":1122680,"name":"Kuiyang Zheng","orcid":"0000-0002-1896-7485","position":7,"is_corresponding":false},{"id":1122681,"name":"Hongbo Guo","orcid":"0009-0006-9241-1414","position":8,"is_corresponding":false},{"id":1122682,"name":"Wenshi Wang","orcid":"0000-0002-7330-262X","position":9,"is_corresponding":false},{"id":1122674,"name":"Jikai Zhang","orcid":"0009-0009-8889-0039","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T01:14:55.198227Z","pmid":"38019020","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":[]}