LHPP-mediated inorganic pyrophosphate hydrolysis-driven lysosomal acidification in astrocytes regulates adult neurogenesis

Longze Sha; Jing Li; Hui Shen; Qingyu Wang; Peixin Meng; Xiuneng Zhang; Yu Deng; Wanwan Zhu; Qi Xu

doi:10.1016/j.celrep.2023.112975

LHPP-mediated inorganic pyrophosphate hydrolysis-driven lysosomal acidification in astrocytes regulates adult neurogenesis

Cell Rep. 2023 Aug 29;42(8):112975. doi: 10.1016/j.celrep.2023.112975. Epub 2023 Aug 12.

Authors

Longze Sha¹, Jing Li², Hui Shen³, Qingyu Wang⁴, Peixin Meng⁴, Xiuneng Zhang⁴, Yu Deng⁴, Wanwan Zhu¹, Qi Xu⁵

Affiliations

¹ 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.
² The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China.
³ 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.
⁴ 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.
⁵ 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. Electronic address: xuqi@pumc.edu.cn.

PMID: 37573508
DOI: 10.1016/j.celrep.2023.112975

Abstract

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.

Keywords: CP: Cell biology; CP: Neuroscience.