{"doi":"10.1165/rcmb.2025-0532ed","title":"E3 ubiquitin ligases and asthma relief","abstract":"Asthma is marked by airway hyperresponsiveness, inflammation, mucus secretion and tissue remodeling.These pathological changes in the lungs are principally orchestrated by the actions of multiple exogenous and endogenous stimuli, including cytokines, pathogenand damage-associated molecular patterns that can activate receptors on immune and non-immune cells in the lung and transduce complex intracellular signaling cascades resulting in modulation of effector protein expression and/or functions.These pathways are finely regulated by post-translational modifications such as phosphorylation, ubiquitination, and sumoylation.Ubiquitination of proteins includes sequential actions of E1-activating, E2-conjugating and E3-ligase enzymes that ultimately insert ubiquitin moieties on target proteins.E3 ubiquitin ligases confer substrate specificity in ubiquitination process and mark target proteins for degradation, altering their location within cellular compartments or modulating their physiological activity.Consequently, E3 ligases are attractive targets in manipulating ubiquitination that plays a critical role in the initiation and progression of chronic inflammatory diseases.In murine models of asthma, E3 ligases can act as both promoters and inhibitors of asthma progression by modulating cellular function via modifications to specific target proteins (1, 2).For example, MID1, TRIM27 and Parkin ubiquitinate PP2A, NLRP3 and NF-B, respectively, and promote airway hyperresponsiveness, epithelial barrier dysfunction and inflammation.In contrast, respective ubiquitination of STAT6, pJAK1 and NLRP3 by PPAR, CUL5 and TRIM31 inhibits IgE synthesis and Th2 differentiation.Diverse E3 ligases can modulate asthma progression by targeting specific substrates to repattern complex and interconnected signaling pathways, thus targeting specific E3 ligases is an intriguing therapeutic concept in asthma.Here, Wang and colleagues (3) detail the role of Pellinos 1 (PELI1), an E3 ubiquitin ligase, in a murine model of asthma.PELI1 is an E3 ligase belonging to the Pellinos family that regulates multiple signaling networks (4).PELI1 is consistently activated by diverse receptor-driven signal transduction pathways.In this regard, TLR3-and TLR4-dependent signaling are critical regulators of PELI1 (5).PELI mediates ubiquitination of effector proteins through K48 or K63 linkage of the ubiquitin moiety (6).Overexpression of PELI1 also drives sumoylation, a post-translational modification involving addition of SUMO-","journal":"American Journal of Respiratory Cell and Molecular Biology","year":2025,"id":577531,"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":0.9557,"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":373524,"name":"Ajay P. Nayak","orcid":"0000-0003-3437-0096","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:58:04.622308Z","pmid":"41071167","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":[]}