首页|Mechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis
Mechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis
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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 frame shift 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 sug-gested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2.This study helps under-stand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phos-phorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.
Hao Sun、Xuan Xu、Junyu Luo、Tingbin Ma、Jiaming Cui、Mugen Liu、Bo Xiong、Shujia Zhu、Jing-Yu Liu
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College of Life Science and Technology,Huazhong Univer-sity of Science and Technology(HUST),Wuhan 430074,China
Institute of Neuroscience,State Key Laboratory of Neuro-science,Center for Excellence in Brain Science and Intelli-gence Technology,Chinese Academy of Sciences,Shanghai 200031,China
Department of Forensic Medicine,Tongji Medical College,HUST,Wuhan 430030,China
National Natural Science Foundation of ChinaShanghai Municipal Science and Technology Major Project
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