A Role for the Proton-coupled Folate Transporter (PCFT-SLC46A1) in Folate Receptor-mediated Endocytosis

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2008 Dec 17

PMID 19074442

Citations 76

Authors

Rongbao Zhao

Sang Hee Min

Yanhua Wang

Estela Campanella

Philip S Low

I David Goldman

Affiliations

Soon will be listed here.

Abstract

Recently, this laboratory identified a proton-coupled folate transporter (PCFT), with optimal activity at low pH. PCFT is critical to intestinal folate absorption and transport into the central nervous system because there are loss-of-function mutations in this gene in the autosomal recessive disorder, hereditary folate malabsorption. The current study addresses the role PCFT might play in another transport pathway, folate receptor (FR)-mediated endocytosis. FRalpha cDNA was transfected into novel PCFT(+) and PCFT(-) HeLa sublines. FRalpha was shown to bind and trap folates in vesicles but with minimal export into the cytosol in PCFT(-) cells. Cotransfection of FRalpha and PCFT resulted in enhanced folate transport into cytosol as compared with transfection of FRalpha alone. Probenecid did not inhibit folate binding to FR, but inhibited PCFT-mediated transport at endosomal pH, and blocked FRalpha-mediated transport into the cytosol. FRalpha and PCFT co-localized to the endosomal compartment. These observations (i) indicate that PCFT plays a role in FRalpha-mediated endocytosis by serving as a route of export of folates from acidified endosomes and (ii) provide a functional role for PCFT in tissues in which it is expressed, such as the choroid plexus, where the extracellular milieu is at neutral pH.

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References

Umapathy N, Gnana-Prakasam J, Martin P, Mysona B, Dun Y, Smith S . Cloning and functional characterization of the proton-coupled electrogenic folate transporter and analysis of its expression in retinal cell types. Invest Ophthalmol Vis Sci. 2007; 48(11):5299-305. PMC: 3850295. DOI: 10.1167/iovs.07-0288. View

Ramaekers V, Rothenberg S, Sequeira J, Opladen T, Blau N, Quadros E . Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005; 352(19):1985-91. DOI: 10.1056/NEJMoa043160. View

Moretti P, Peters S, Del Gaudio D, Sahoo T, Hyland K, Bottiglieri T . Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency. J Autism Dev Disord. 2007; 38(6):1170-7. PMC: 4131536. DOI: 10.1007/s10803-007-0492-z. View

Segal M . The choroid plexuses and the barriers between the blood and the cerebrospinal fluid. Cell Mol Neurobiol. 2000; 20(2):183-96. PMC: 11537546. DOI: 10.1023/a:1007045605751. View

Shayeghi M, Latunde-Dada G, Oakhill J, Laftah A, Takeuchi K, Halliday N . Identification of an intestinal heme transporter. Cell. 2005; 122(5):789-801. DOI: 10.1016/j.cell.2005.06.025. View

Lasry I, Berman B, Straussberg R, Sofer Y, Bessler H, Sharkia M . A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function. Blood. 2008; 112(5):2055-61. DOI: 10.1182/blood-2008-04-150276. View

Qiu A, Jansen M, Sakaris A, Min S, Chattopadhyay S, Tsai E . Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006; 127(5):917-28. DOI: 10.1016/j.cell.2006.09.041. View

Min S, Oh S, Karp G, Poncz M, Zhao R, Goldman I . The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption. J Pediatr. 2008; 153(3):435-7. PMC: 3835188. DOI: 10.1016/j.jpeds.2008.04.009. View

Spector R, LORENZO A . Folate transport by the choroid plexus in vitro. Science. 1975; 187(4176):540-2. DOI: 10.1126/science.1167256. View

10.

Kamen B, Smith A, Anderson R . The folate receptor works in tandem with a probenecid-sensitive carrier in MA104 cells in vitro. J Clin Invest. 1991; 87(4):1442-9. PMC: 295193. DOI: 10.1172/JCI115150. View

11.

Gunshin H, Fujiwara Y, Custodio A, Direnzo C, Robine S, Andrews N . Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest. 2005; 115(5):1258-66. PMC: 1077176. DOI: 10.1172/JCI24356. View

12.

Yang J, Chen H, Vlahov I, Cheng J, Low P . Characterization of the pH of folate receptor-containing endosomes and the rate of hydrolysis of internalized acid-labile folate-drug conjugates. J Pharmacol Exp Ther. 2007; 321(2):462-8. DOI: 10.1124/jpet.106.117648. View

13.

Salazar M, Ratnam M . The folate receptor: what does it promise in tissue-targeted therapeutics?. Cancer Metastasis Rev. 2007; 26(1):141-52. DOI: 10.1007/s10555-007-9048-0. View

14.

Leamon C, Pastan I, Low P . Cytotoxicity of folate-Pseudomonas exotoxin conjugates toward tumor cells. Contribution of translocation domain. J Biol Chem. 1993; 268(33):24847-54. View

15.

Patrick T, Kranz D, Van Dyke T, Roy E . Folate receptors as potential therapeutic targets in choroid plexus tumors of SV40 transgenic mice. J Neurooncol. 1997; 32(2):111-23. DOI: 10.1023/a:1005713115147. View

16.

Kamen B, Wang M, Streckfuss A, Peryea X, Anderson R . Delivery of folates to the cytoplasm of MA104 cells is mediated by a surface membrane receptor that recycles. J Biol Chem. 1988; 263(27):13602-9. View

17.

Kamen B, Smith A . A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev. 2004; 56(8):1085-97. DOI: 10.1016/j.addr.2004.01.002. View

18.

Ramaekers V, Blau N . Cerebral folate deficiency. Dev Med Child Neurol. 2004; 46(12):843-51. DOI: 10.1017/s0012162204001471. View

19.

Fleming M, Trenor 3rd C, Su M, Foernzler D, Beier D, Dietrich W . Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997; 16(4):383-6. DOI: 10.1038/ng0897-383. View

20.

Zhao R, Seither R, Brigle K, Sharina I, Wang P, Goldman I . Impact of overexpression of the reduced folate carrier (RFC1), an anion exchanger, on concentrative transport in murine L1210 leukemia cells. J Biol Chem. 1997; 272(34):21207-12. DOI: 10.1074/jbc.272.34.21207. View