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

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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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2024-12-30
DOI
https://doi.org/10.1038/s41392-024-02076-9
Citations
30
Primary Topic
Sphingolipid Metabolism and Signaling
Type
article
Field-Weighted Citation Impact
7.01

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article

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

Mingyu Yang, Kanglai Tang, Jing-tong Lv, Liuli Li et al.
30 citations
Signal Transduction and Targeted Therapy
Sphingolipid Metabolism and Signaling
7.01
article

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

Mingyu Yang, Kanglai Tang, Jing-tong Lv, Liuli Li, Gang He, Yunqing Tang, Huan Chen, Jindong Tan, Xiangli Zhao, Hai‐long Piao, C.-J. Liu, Kun Zhao, E.-A. Kim, Xuting Bian, Chenke Zhang, Yujianan Chen, Ruihua Shi, Youxing Shi, Hongming Miao, Feng Xu, Aubryanna Hettinghouse, Yan Xiang, Hong Tang, Xia Kang, Teng Wang, Feng Wang, Fan Li, Xiao Ye, Yue Qin, Kaidi Wang, Mei Zhou, Lin Guo, Binghua Zhou, Wan Chen, Pan Huang, Taotao Liang, Wen-yu Fu
article en
30 citations

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.

Signal Transduction and Targeted TherapyVol. 9(1)
Qingdao University (CN), Army Medical University (CN), Dalian Institute of Chemical Physics (CN), Chinese Academy of Sciences (CN), Southwest Medical University (CN), Yale University (US), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), Southwest Hospital (CN), Dongfeng Motor Group (China) (CN), New York University (US), Chongqing Medical University (CN)
NYU Langone Medical Center, York University, National Natural Science Foundation of China, Fudan University, Chongqing Medical University, Wuhan University, Southwest Hospital, Army Medical University, Centre Scientifique et Technique du Bâtiment, National Institutes of Health, School of Pharmacy, Fudan University
Clean water and sanitation
Openalex Percentile: Top 2%
Sphingolipid Metabolism and Signaling
7.01
DOIOpen Access PDFOpenAlex
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