Mechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis.
10.1007/s12264-022-00893-y
- Author:
Hao SUN
1
;
Xuan XU
2
;
Junyu LUO
1
;
Tingbin MA
2
;
Jiaming CUI
2
;
Mugen LIU
1
;
Bo XIONG
3
;
Shujia ZHU
4
;
Jing-Yu LIU
5
Author Information
1. College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, 430074, China.
2. Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
3. Department of Forensic Medicine, Tongji Medical College, HUST, Wuhan, 430030, China.
4. Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China. shujiazhu@ion.ac.cn.
5. Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China. liujy@ion.ac.cn.
- Publication Type:Journal Article
- Keywords:
Mutation;
Phosphorylation;
Pi dyshomeostasis;
PiT2-loop7;
Primary familial brain calcification
- MeSH:
Humans;
Cell Membrane;
Mutation, Missense;
Phosphates/metabolism*;
Sodium-Phosphate Cotransporter Proteins, Type III/genetics*
- From:
Neuroscience Bulletin
2023;39(1):57-68
- CountryChina
- Language:English
-
Abstract:
PiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase (AMPK)- or protein kinase B (AKT)-mediated PiT2 phosphorylation. In contrast, the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities. These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2. This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.
