2. Academic Validation
  3. Malate initiates a proton-sensing pathway essential for pH regulation of inflammation

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

  • Signal Transduct Target Ther. 2024 Dec 30;9(1):367. doi: 10.1038/s41392-024-02076-9.
Yu-Jia-Nan Chen # 1 2 3 4 5,  Rong-Chen Shi # 6 7,  Yuan-Cai Xiang # 6 7 8,  Li Fan # 9 10,  Hong Tang 9,  Gang He 9,  Mei Zhou 9,  Xin-Zhe Feng 11,  Jin-Dong Tan 9 12,  Pan Huang 9,  Xiao Ye 9,  Kun Zhao 6 7,  Wen-Yu Fu 11 13,  Liu-Li Li 6,  Xu-Ting Bian 9,  Huan Chen 14,  Feng Wang 9,  Teng Wang 6 7,  Chen-Ke Zhang 9,  Bing-Hua Zhou 9,  Wan Chen 9,  Tao-Tao Liang 9,  Jing-Tong Lv 9,  Xia Kang 9 6 7,  You-Xing Shi 9,  Ellen Kim 11,  Yin-Hua Qin 15,  Aubryanna Hettinghouse 11,  Kai-di Wang 11 16,  Xiang-Li Zhao 11 13,  Ming-Yu Yang 9,  Yu-Zhen Tang 9,  Hai-Long Piao 14,  Lin Guo 17,  Chuan-Ju Liu 18 19,  Hong-Ming Miao 20 21,  Kang-Lai Tang 22
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China. chenyujiananjade@hotmail.com.
  • 2 Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China. chenyujiananjade@hotmail.com.
  • 3 Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA. chenyujiananjade@hotmail.com.
  • 4 NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases & Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China. chenyujiananjade@hotmail.com.
  • 5 Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China. chenyujiananjade@hotmail.com.
  • 6 Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China.
  • 7 Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China.
  • 8 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, 646000, China.
  • 9 Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China.
  • 10 NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases & Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China.
  • 11 Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA.
  • 12 Department of Rehabilitation Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 13 Department of Orthopedics and Rehabilitations, Yale University School of Medicine, New Haven, CT, 06519, USA.
  • 14 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
  • 15 Department of Anatomy, Engineering Research Center for Organ Intelligent Biological Manufacturing of Chongqing, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University, Chongqing, 400038, China.
  • 16 Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266000, China.
  • 17 Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China. guolin6212@163.com.
  • 18 Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA. chuan-ju.liu@yale.edu.
  • 19 Department of Orthopedics and Rehabilitations, Yale University School of Medicine, New Haven, CT, 06519, USA. chuan-ju.liu@yale.edu.
  • 20 Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China. hongmingmiao@sina.com.
  • 21 Jinfeng Laboratory, Chongqing, 401329, China. hongmingmiao@sina.com.
  • 22 Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China. tangkanglai@hotmail.com.
  • # Contributed equally.
PMID: 39737965 DOI: 10.1038/s41392-024-02076-9
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.

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