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

作　　者：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 

机构地区：[1]Department of Orthopedic Surgery/Sports Medicine Center,Southwest Hospital,Army Medical University,Chongqing 400038,China [2]Department of Pathophysiology,College of High Altitude Military Medicine,Army Medical University,Chongqing 400038,China [3]Department of Orthopedic Surgery,NYU Grossman School of Medicine,New York,NY 10003,USA [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 [5]Department of Biochemistry and Molecular Biology,Army Medical University,Chongqing 400038,China [6]Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Southwest Medical University,Luzhou,Sichuan 646000,China [7]Department of Rehabilitation Medicine,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China [8]Department of Orthopedics and Rehabilitations,Yale University School of Medicine,New Haven,CT 06519,USA [9]CAS Key Laboratory of Separation Science for Analytical Chemistry,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian 116023,China [10]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 [11]Department of Medical Experimental Center,Qilu Hospital(Qingdao),Cheeloo College of Medicine,Shandong University,Qingdao 266000,China [12]Jinfeng Laboratory,Chongqing 401329,China

出　　处：《Signal Transduction and Targeted Therapy》2025年第1期446-470,共25页信号转导与靶向治疗(英文)

基　　金：supported by grants from the National Natural Science Foundation of China 82130071,82072516(Kanglai Tang);Sports Injury Repair and Reconstruction Research Innovative Team 41CZDH,Personalized Training Program of Leading Talent Training Object 414ZB2(Kanglai Tang);National Key R&D Program of China 2021YFC2401300(Lin Guo);National Natural Science Foundation of China 82173134(Hongming Miao);The Funding of Jinfeng Laboratory and Chongqing Outstanding Youth Fund CSTB2022NSCQ-JQX0010(Hongming Miao);NIH research grants R01AR062207,R01AR061484,R01AR076900,R01NS103931(Chuanju Liu);NIH research grants 1S10OD010582-01A1(Beatrix Ueberheide).

摘　　要：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 BiPIRF2BP2 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.Thesefindings 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.

关 键 词：interaction restrained ANALOGUES 

分 类 号：O62[理学—有机化学]