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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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-12-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-024-02076-9 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yu-jia-nan Chen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-544fdb0fa40841ad9dd580adcba28194 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-544fdb0fa40841ad9dd580adcba281942025-01-05T12:47:54ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352024-12-019112510.1038/s41392-024-02076-9Malate initiates a proton-sensing pathway essential for pH regulation of inflammationYu-jia-nan Chen0Rong-chen Shi1Yuan-cai Xiang2Li Fan3Hong Tang4Gang He5Mei Zhou6Xin-zhe Feng7Jin-dong Tan8Pan Huang9Xiao Ye10Kun Zhao11Wen-yu Fu12Liu-li Li13Xu-ting Bian14Huan Chen15Feng Wang16Teng Wang17Chen-ke Zhang18Bing-hua Zhou19Wan Chen20Tao-tao Liang21Jing-tong Lv22Xia Kang23You-xing Shi24Ellen Kim25Yin-hua Qin26Aubryanna Hettinghouse27Kai-di Wang28Xiang-li Zhao29Ming-yu Yang30Yu-zhen Tang31Hai-long Piao32Lin Guo33Chuan-ju Liu34Hong-ming Miao35Kang-lai Tang36Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Pathophysiology, College of High Altitude Military Medicine, Army Medical UniversityDepartment of Pathophysiology, College of High Altitude Military Medicine, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery, NYU Grossman School of MedicineDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Pathophysiology, College of High Altitude Military Medicine, Army Medical UniversityDepartment of Orthopedic Surgery, NYU Grossman School of MedicineDepartment of Pathophysiology, College of High Altitude Military Medicine, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityCAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of SciencesDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Pathophysiology, College of High Altitude Military Medicine, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery, NYU Grossman School of MedicineDepartment of Anatomy, Engineering Research Center for Organ Intelligent Biological Manufacturing of Chongqing, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical UniversityDepartment of Orthopedic Surgery, NYU Grossman School of MedicineDepartment of Orthopedic Surgery, NYU Grossman School of MedicineDepartment of Orthopedic Surgery, NYU Grossman School of MedicineDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityCAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of SciencesDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityDepartment of Orthopedic Surgery, NYU Grossman School of MedicineDepartment of Pathophysiology, College of High Altitude Military Medicine, Army Medical UniversityDepartment of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical UniversityAbstract 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.https://doi.org/10.1038/s41392-024-02076-9 |
| spellingShingle | 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 Malate initiates a proton-sensing pathway essential for pH regulation of inflammation Signal Transduction and Targeted Therapy |
| title | Malate initiates a proton-sensing pathway essential for pH regulation of inflammation |
| title_full | Malate initiates a proton-sensing pathway essential for pH regulation of inflammation |
| title_fullStr | Malate initiates a proton-sensing pathway essential for pH regulation of inflammation |
| title_full_unstemmed | Malate initiates a proton-sensing pathway essential for pH regulation of inflammation |
| title_short | Malate initiates a proton-sensing pathway essential for pH regulation of inflammation |
| title_sort | malate initiates a proton sensing pathway essential for ph regulation of inflammation |
| url | https://doi.org/10.1038/s41392-024-02076-9 |
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