Malate initiates a proton-sensing pathway essential for pH regulation of inflammation

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 mac...

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Main Authors: Yu-jia-nan Chen, Rong-chen Shi, Yuan-cai Xiang, Li Fan, Hong Tang, Gang He, Mei Zhou, Xin-zhe Feng, Jin-dong Tan, Pan Huang, Xiao Ye, Kun Zhao, Wen-yu Fu, Liu-li Li, Xu-ting Bian, Huan Chen, Feng Wang, Teng Wang, Chen-ke Zhang, Bing-hua Zhou, Wan Chen, Tao-tao Liang, Jing-tong Lv, Xia Kang, You-xing Shi, Ellen Kim, Yin-hua Qin, Aubryanna Hettinghouse, Kai-di Wang, Xiang-li Zhao, Ming-yu Yang, Yu-zhen Tang, Hai-long Piao, Lin Guo, Chuan-ju Liu, Hong-ming Miao, Kang-lai Tang
Format: Article
Language:English
Published: Nature Publishing Group 2024-12-01
Series:Signal Transduction and Targeted Therapy
Online Access:https://doi.org/10.1038/s41392-024-02076-9
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Summary: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.
ISSN:2059-3635

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