GPNMB and ATP6V1A interact to mediate microglia phagocytosis of multiple types of pathological particles
Mei Liu,
Jianping Zhu,
Jiawei Zheng,
Xuan Han,
Lijuan Jiang,
Xiangzhen Tong,
Yue Ke,
Zhipeng Guo,
Weiyuan Huang,
Jin Cong,
Meiqiu Liu,
Su-Yan Lin,
Shuang Zhu,
Li Mei,
Xingmei Zhang,
Wangming Zhang,
Wen-Jun Xin,
Zhenhai Zhang,
Yanwu Guo,
Rongqing Chen
Affiliations
Mei Liu
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Jianping Zhu
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Jiawei Zheng
The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Xuan Han
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Lijuan Jiang
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Xiangzhen Tong
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Yue Ke
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Zhipeng Guo
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Weiyuan Huang
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Jin Cong
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Meiqiu Liu
Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Su-Yan Lin
Guangdong Province Key Laboratory of Brain Function and Disease, Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
Shuang Zhu
Department of Joint and Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
Li Mei
Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 519041, China
Xingmei Zhang
Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Wangming Zhang
The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
Wen-Jun Xin
Guangdong Province Key Laboratory of Brain Function and Disease, Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
Zhenhai Zhang
Center for Precision Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 519041, China; Corresponding author
Yanwu Guo
The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Corresponding author
Rongqing Chen
The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Corresponding author
Summary: Pronounced elevation of glycoprotein non-metastatic melanoma B (GPNMB) is a common phenomenon in a variety of brain diseases, but the expression patterns, functions, and molecular signaling of GPNMB have not been well studied. Here, we showed that pathological factors, including neuronal degeneration caused by seizures, caspase-3-induced neuronal apoptosis, neuronal debris, and β-amyloid, induced “on-demand” GPNMB expression in hippocampal microglia. Genetic ablation of GPNMB did not affect acute seizures but worsened chronic epileptogenesis. We found that GPNMB functioned in phagocytosis, deficiency of which resulted in defects in both phagocytic engulfment and degradation. GPNMB could be internalized into cells, where it wrapped engulfed pathogenic particles and presented them to lysosomes through interaction with lysosomal vacuolar-type proton ATPase catalytic subunit A (ATP6V1A). Activating ATP6V1A was able to rescue GPNMB-deficiency-caused phagocytosis impairment. Thus, microglial GPNMB-ATP6V1A might be a common treatment target of a batch of chronic neurological disorders, and clearing the degenerative neurons might be more valuable than reserving them to protect the brain.
