Interplay between primary familial brain calcification-associated SLC20A2 and XPR1 phosphate transporters requires inositol polyphosphates for control of cellular phosphate homeostasis

Abstract

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. 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. The solute carrier (SLC) SLC20 and SLC53 family genes encode three cell surface multitransmembrane proteins known as PiT1/SLC20A1, PiT2/SLC20A2, and polytropic retrovirus receptor 1 (XPR1)/SLC53A1, which were shown to transport phosphate (1Giovannini D. Touhami J. Charnet P. Sitbon M. Battini J.L. Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans.Cell Rep. 2013; 3 (23791524): 1866-187310.1016/j.celrep.2013.05.035Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 2Kavanaugh M.P. Miller D.G. Zhang W. Law W. Kozak S.L. Kabat D. Miller A.D. Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters.Proc. Natl. Acad. Sci. U.S.A. 1994; 91 (8041748): 7071-707510.1073/pnas.91.15.7071Crossref PubMed Scopus (500) Google Scholar, 3Olah Z. Lehel C. Anderson W.B. Eiden M.V. Wilson C.A. 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PubMed Scopus Google and XPR1 transporters a M.P. Kabat D. and characterization of a phosphate receptor Full Text PDF PubMed Scopus Google and SLC20 transporters are in cellular phosphate homeostasis L. The SLC20 family of as and PubMed Scopus Google direct evidence is missing. A role for to to with inositol A. A. M. A. of phosphate homeostasis by inositol polyphosphate PubMed Scopus Google which are of intracellular phosphate C. A. phosphate the inositol pyrophosphate Sci. Full Text Full Text PDF PubMed Scopus Google SLC20A1 and SLC20A2 are sodium-dependent transporters of the which phosphate the M.P. Miller D.G. Zhang W. Law W. Kozak S.L. Kabat D. Miller A.D. Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters.Proc. Natl. Acad. Sci. U.S.A. 1994; 91 (8041748): 7071-707510.1073/pnas.91.15.7071Crossref PubMed Scopus (500) Google Scholar, 3Olah Z. Lehel C. Anderson W.B. Eiden M.V. Wilson C.A. The cellular receptor for gibbon ape leukemia virus is a novel high affinity sodium-dependent phosphate transporter.J. Biol. Chem. 1994; 269 (7929240): 25426-25431Abstract Full Text PDF PubMed Google XPR1 phosphate efflux (1Giovannini D. Touhami J. Charnet P. Sitbon M. Battini J.L. Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans.Cell Rep. 2013; 3 (23791524): 1866-187310.1016/j.celrep.2013.05.035Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, S. of the xenotropic polytropic virus receptor 1 (XPR1) in to phosphate PubMed Scopus Google Scholar) with a is that the of transport is by both the intracellular and phosphate which constant The intracellular of phosphate is role in key in cells. phosphate is a of and and is for intracellular and phosphate is a with of the found in and and as a for cell and S. A. M. P. J. L. The of phosphate as a in and cell in Sci. PubMed Scopus Google SLC20A1 and SLC20A2 an in both in phosphate A. S. S. J. L. of the sodium-dependent transporters and of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and in S. L. A. C. S. the phosphate is an genetic of and PubMed Scopus Google Scholar, A. P. K. S. S. S. M. M. J. of overexpression on phosphate and PubMed Scopus Google and are in of the sodium-dependent phosphate in cell PubMed Scopus Google Scholar, M. cell calcification and SLC20 phosphate of and PubMed Scopus Google familial brain calcification is a genetic characterized by brain calcification in with phosphate and levels J. familial brain M.P. K. A. of Scholar) and is associated with neuropsychiatric and symptoms. on calcification the basal and of the the and and the cerebral C. D. A. D. T. D. D. calcification and to and and J. Genet. Genet. PubMed Scopus Google is a with phosphate in of and and respectively. genes with SLC20A2 and XPR1 A. D. B. A. C. S. C. in XPR1 primary familial brain calcification associated with altered phosphate Genet. PubMed Scopus Google Scholar, C. L. 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Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans.Cell Rep. 2013; 3 (23791524): 1866-187310.1016/j.celrep.2013.05.035Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, A. D. B. A. C. S. C. in XPR1 primary familial brain calcification associated with altered phosphate Genet. PubMed Scopus Google Scholar, M. D. Touhami J. L. A. T. D. D. Battini J.L. Sitbon M. XPR1 are a of primary familial brain PubMed Scopus Google Scholar, D. M. C. Touhami J. Battini J.L. Sitbon M. Characterization of variants of the in with primary familial brain Rep. PubMed Scopus Google phosphate that overexpression of human SLC20A2 to a in phosphate uptake, as expected, with phosphate uptake to basal levels with the SLC20A2 that variants altered phosphate uptake, with on SLC20A2 and phosphate the in phosphate uptake for WT SLC20A2 with an in phosphate efflux were with SLC20A1 phosphate efflux with the SLC20A2 variants to a interplay between phosphate uptake and efflux. of the and SLC20A2 variants with a in phosphate uptake, with phosphate efflux to controls in The phosphate efflux a cellular that maintained phosphate homeostasis. SLC20A2 and XPR1 are both associated with and both in phosphate we they or this we human in which SLC20A2 or XPR1 genes were by of SLC20A2 and XPR1 at the by and by cell to infection by with amphotropic murine leukemia virus or xenotropic murine leukemia virus of SLC20A1 and XPR1 in SLC20A2 KO infection a for both transporters the receptor by the virus G We also by with a retroviral the SLC20A2 in both and infection by A and a but in SLC20A1 to and in expected, XPR1 KO a in phosphate efflux and on uptake, which the role of XPR1 as the phosphate and we found that overexpression of human SLC20A2 to a in phosphate uptake, with depletion of SLC20A2 only a of phosphate uptake most likely to the of the in phosphate uptake in with an in phosphate efflux basal levels of XPR1 in were with this phosphate efflux, of SLC20A2 phosphate efflux in SLC20A2 KO XPR1 at the phosphate efflux on in but not in XPR1 KO increased phosphate uptake in both cell evidence that only as a sodium-dependent phosphate also phosphate efflux or with a cellular that phosphate homeostasis, we found that the intracellular levels of both phosphate and ATP were in and SLC20A2 KO and phosphate and ATP levels were in XPR1 KO with with a role for and not as a of intracellular phosphate for phosphate homeostasis in cells. of phosphate were shown to phosphate efflux (1Giovannini D. 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The is a receptor for Full Text Full Text PDF PubMed Scopus Google Scholar) or in the retroviral A.D. retroviral for gene and Google SLC20A2 variants were at with two of the with the were by with the WT or SLC20A2 the A. Sitbon M. Battini J.L. in the murine leukemia virus that to mouse and human PubMed Scopus Google and the (4Battini J.L. Rasko J.E. Miller A.D. A human cell-surface receptor for xenotropic and polytropic murine leukemia viruses: possible role in G protein-coupled signal transduction.Proc Natl Acad Sci U.S.A. 1999; 96 (9990033): 1385-139010.1073/pnas.96.4.1385Crossref PubMed Scopus (184) Google were after and for human cell the were as A. S. D. Battini J.L. Sitbon M. and are for infection by primary Rep. PubMed Scopus Google or gibbon ape leukemia virus were to 1 the in a for were in and with and on a the of were of intracellular ATP levels, were in a were with for The were with and for in or with 1 phosphate The the to the of a were with 20 1 inhibitor of phosphate were in a The were on three with and for at in of with were to the with the phosphate ATP and phosphate were to the as with the of phosphate transporters at the as (1Giovannini D. Touhami J. Charnet P. Sitbon M. Battini J.L. Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans.Cell Rep. 2013; 3 (23791524): 1866-187310.1016/j.celrep.2013.05.035Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, A. D. B. A. C. S. C. in XPR1 primary familial brain calcification associated with altered phosphate Genet. PubMed Scopus Google Scholar, M. D. Touhami J. L. A. T. D. D. Battini J.L. Sitbon M. XPR1 are a of primary familial brain PubMed Scopus Google Scholar, D. M. C. Touhami J. Battini J.L. Sitbon M. Characterization of variants of the in with primary familial brain Rep. PubMed Scopus Google and to a mouse and to and respectively. were and as (1Giovannini D. Touhami J. Charnet P. Sitbon M. Battini J.L. Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans.Cell Rep. 2013; 3 (23791524): 1866-187310.1016/j.celrep.2013.05.035Abstract Full Text Full Text PDF PubMed Scopus (85) Google were with 1 in in the and at for with were with and for 20 on with were in and on a or a uptake and efflux in and were as (1Giovannini D. Touhami J. Charnet P. Sitbon M. Battini J.L. Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans.Cell Rep. 2013; 3 (23791524): 1866-187310.1016/j.celrep.2013.05.035Abstract Full Text Full Text PDF PubMed Scopus (85) Google uptake as the of cellular to The of phosphate efflux as the of to cellular uptake and efflux in were as A. D. B. A. C. S. 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