{"doi":"10.1038/s41392-024-02076-9","title":"Malate initiates a proton-sensing pathway essential for pH regulation of inflammation","abstract":"Metabolites can double as a signaling modality that initiates physiological adaptations. Metabolism, a chemical language encoding biological information, has been recognized as a powerful principle directing inflammatory responses. Cytosolic pH is a regulator of inflammatory response in macrophages. Here, we found that L-malate exerts anti-inflammatory effect via BiP-IRF2BP2 signaling, which is a sensor of cytosolic pH in macrophages. First, L-malate, a TCA intermediate upregulated in pro-inflammatory macrophages, was identified as a potent anti-inflammatory metabolite through initial screening. Subsequent screening with DARTS and MS led to the isolation of L-malate-BiP binding. Further screening through protein‒protein interaction microarrays identified a L-malate-restrained coupling of BiP with IRF2BP2, a known anti-inflammatory protein. Interestingly, pH reduction, which promotes carboxyl protonation of L-malate, facilitates L-malate and carboxylate analogues such as succinate to bind BiP, and disrupt BiP-IRF2BP2 interaction in a carboxyl-dependent manner. Both L-malate and acidification inhibit BiP-IRF2BP2 interaction, and protect IRF2BP2 from BiP-driven degradation in macrophages. Furthermore, both in vitro and in vivo, BiP-IRF2BP2 signal is required for effects of both L-malate and pH on inflammatory responses. These findings reveal a previously unrecognized, proton/carboxylate dual sensing pathway wherein pH and L-malate regulate inflammatory responses, indicating the role of certain carboxylate metabolites as adaptors in the proton biosensing by interactions between macromolecules.","journal":"Signal Transduction and Targeted Therapy","year":2024,"id":420540,"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":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":284026,"name":"Ruihua Shi","orcid":"0000-0003-4977-8801","position":1,"is_corresponding":false},{"id":1212683,"name":"Yuan-cai Xiang","orcid":null,"position":2,"is_corresponding":false},{"id":1211977,"name":"Fan Li","orcid":"0000-0002-7998-0093","position":3,"is_corresponding":false},{"id":1211978,"name":"Hong Tang","orcid":"0000-0003-0011-6575","position":4,"is_corresponding":false},{"id":1211979,"name":"Gang He","orcid":"0000-0001-9806-4069","position":5,"is_corresponding":false},{"id":45454,"name":"Mei Zhou","orcid":"0000-0002-8510-5287","position":6,"is_corresponding":false},{"id":1211980,"name":"Feng Xu","orcid":"0000-0003-2016-7521","position":7,"is_corresponding":false},{"id":1211981,"name":"Jindong Tan","orcid":"0000-0003-0339-8811","position":8,"is_corresponding":false},{"id":1211982,"name":"Pan Huang","orcid":"0009-0007-8468-1227","position":9,"is_corresponding":false},{"id":1212684,"name":"Xiao Ye","orcid":null,"position":10,"is_corresponding":false},{"id":310264,"name":"Kun Zhao","orcid":"0000-0003-3928-1981","position":11,"is_corresponding":false},{"id":834661,"name":"Wen-yu Fu","orcid":null,"position":12,"is_corresponding":false},{"id":1212685,"name":"Liuli Li","orcid":null,"position":13,"is_corresponding":false},{"id":1211983,"name":"Xuting Bian","orcid":"0000-0002-9234-4913","position":14,"is_corresponding":false},{"id":1186100,"name":"Huan Chen","orcid":"0000-0003-3910-3712","position":15,"is_corresponding":false},{"id":1211984,"name":"Feng Wang","orcid":"0000-0002-7793-0367","position":16,"is_corresponding":false},{"id":1211985,"name":"Teng Wang","orcid":"0000-0002-8521-0749","position":17,"is_corresponding":false},{"id":1212686,"name":"Chenke Zhang","orcid":null,"position":18,"is_corresponding":false},{"id":1211986,"name":"Binghua Zhou","orcid":"0000-0001-6353-6855","position":19,"is_corresponding":false},{"id":611896,"name":"Wan Chen","orcid":"0000-0002-6140-8136","position":20,"is_corresponding":false},{"id":1211987,"name":"Taotao Liang","orcid":"0000-0002-8905-7630","position":21,"is_corresponding":false},{"id":1212687,"name":"Jing-tong Lv","orcid":null,"position":22,"is_corresponding":false},{"id":1211988,"name":"Xia Kang","orcid":"0000-0002-5172-2105","position":23,"is_corresponding":false},{"id":1212688,"name":"Youxing Shi","orcid":null,"position":24,"is_corresponding":false},{"id":544780,"name":"E.-A. 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