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Chen, Y.-J.-N., Shi, R.-C., & Xiang, Y.-C. (2024). Malate initiates a proton-sensing pathway essential for pH regulation of inflammation. Signal Transduction and Targeted Therapy, 9(1), 367. Added by: Dr. Enrique Feoli (05/07/2025, 21:00) Last edited by: Dr. Enrique Feoli (05/07/2025, 21:01) |
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| Resource type: Journal Article DOI: 10.1038/s41392-024-02076-9 ID no. (ISBN etc.): 2059-3635 BibTeX citation key: Chen2024 View all bibliographic details  |
Categories: BioAcyl Corp, BioAcyl Corp Subcategories: Microecoambiente, Microenvironment Keywords: Cell biology, Drug screening, inflammation Creators: Chen, Shi, Xiang Collection: Signal Transduction and Targeted Therapy |
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| Abstract |
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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.
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Publisher: Nature Publishing Group
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