期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 28, 页码 9366-9378出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.011376
关键词
xenotropic and polytropic retrovirus receptor 1 (XPR1); phosphate transporter; primary familial brain calcification (PFBC); phosphate homeostasis; ATP; inositol pyrophosphate; metabolic regulation; SPX domain; efflux transporter; cell metabolism; energy metabolism; anion transport; inositol phosphate
资金
- Labex EpiGenMed [ANR-10-LABX-12-01]
- Consejo Nacional de Ciencia y Tecnologia (CONACYT) [243449/440597]
- Fondation pour la Recherche Medicale (FRM) [FDT20170436884]
- ANR [ANR-17-CE14-0008, ANR-17-CE14-0008-01]
- FRM [DBI201312285579]
- NIH [DK32094]
- Labex GR-Ex [ANR-11-LABX-0051]
- European Union
- Region Normandie through the Recherche Innovation Normandie (RIN 2018)
- Inserm
- Agence Nationale de la Recherche (ANR) [ANR-17-CE14-0008] Funding Source: Agence Nationale de la Recherche (ANR)
- MRC [MR/T028904/1] Funding Source: UKRI
Solute carrier family 20 member 2 (SLC20A2) and xenotropic and polytropic retrovirus receptor 1 (XPR1) are transporters with phosphate uptake and efflux functions, respectively. Both are associated with primary familial brain calcification (PFBC), a genetic disease characterized by cerebral calcium-phosphate deposition and associated with neuropsychiatric symptoms. The association of the two transporters with the same disease suggests that they jointly regulate phosphate fluxes and cellular homeostasis, but direct evidence is missing. Here, we found that cross-talk between SLC20A2 and XPR1 regulates phosphate homeostasis, and we identified XPR1 as a key inositol polyphosphate (IP)-dependent regulator of this process. We found that overexpression of WT SLC20A2 increased phosphate uptake, as expected, but also unexpectedly increased phosphate efflux, whereas PFBC-associated SLC20A2 variants did not. Conversely, SLC20A2 depletion decreased phosphate uptake only slightly, most likely compensated for by the related SLC20A1 transporter, but strongly decreased XPR1-mediated phosphate efflux. The SLC20A2-XPR1 axis maintained constant intracellular phosphate and ATP levels, which both increased in XPR1 KO cells. Elevated ATP levels are a hallmark of altered inositol pyrophosphate (PP-IP) synthesis, and basal ATP levels were restored after phosphate efflux rescue with WT XPR1 but not with XPR1 harboring a mutated PP-IP?binding pocket. Accordingly, inositol hexakisphosphate kinase 1-2 (IP6K1-2) gene inactivation or IP6K inhibitor treatment abolished XPR1-mediated phosphate efflux regulation and homeostasis. Our findings unveil an SLC20A2-XPR1 interplay that depends on IPs such as PP-IPs and controls cellular phosphate homeostasis via the efflux route, and alteration of this interplay likely contributes to PFBC.
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