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 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.
基金项目
National Natural Science Foundation of China(31871262)
Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)
维普
万方数据