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
  • 1. Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China. [email protected].
  • 2. Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China. [email protected].
  • 3. Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA. [email protected].
  • 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. [email protected].
  • 5. Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China. [email protected].
  • 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. [email protected].
  • 18. Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA. [email protected].
  • 19. Department of Orthopedics and Rehabilitations, Yale University School of Medicine, New Haven, CT, 06519, USA. [email protected].
  • 20. Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China. [email protected].
  • 21. Jinfeng Laboratory, Chongqing, 401329, China. [email protected].
  • 22. Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China. [email protected].
  • # 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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