State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China
Jing Li
The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China
Hui Shen
State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center for Translational Medicine, Second Military Medical University, Shanghai 200433, China
Qingyu Wang
State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
Peixin Meng
State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
Xiuneng Zhang
State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
Yu Deng
State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
Wanwan Zhu
State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China
Qi Xu
State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China; Corresponding author
Summary: In bacteria, archaea, protists, and plants, the hydrolysis of pyrophosphate (PPi) by inorganic pyrophosphatase (PPase) can, under stress conditions, substitute for ATP-driven proton flux to generate a proton gradient and induce luminal acidification. However, this strategy is considered to be lost in eukaryotes. Here, we report that LHPP, a poorly understood PPase that exhibits activity at acidic pH, is primarily expressed in astrocytes and partly localized on lysosomal membranes. Under stress conditions, LHPP is recruited to vacuolar ATPase (V-ATPase) and facilitates V-ATPase-dependent proton transport and lysosomal acidification by hydrolyzing PPi. LHPP knockout (KO) mice have no discernable phenotype but are resilient to chronic-stress-induced depression-like behaviors. Mechanistically, LHPP deficiency prevents lysosome-dependent degradation of C/EBPβ and induces the expression of a group of chemokines that promote adult neurogenesis. Together, these findings suggest that LHPP is likely to be a therapeutic target for stress-related brain disease.
