SLC29A3 Membrane Protein Introduction

Introduction of SLC29A3

Solute carrier family 29 member 3 (SLC29A3), also known as Equilibrative nucleoside transporter 3 (ENT3), is a protein that in humans is encoded by the SLC29A3 gene. SLC29A3 protein also contains 11 characteristic transmembrane domains of the ENT family, but they are preceded by a long cytoplasmic N-terminal region not found in SLC29A1 or SLC29A2. The unique N-terminal domain of SLC29A3 contains a conserved putative dileucine-based endosomal/lysosomal targeting motif. SLC29A3 is widely expressed in a range of tissues, including kidney, placenta, breast, colon, testis, fetal liver, fetal spleen, and several neoplastic tissues.

Function of SLC29A3 Membrane Protein

SLC29A3 can function as an equilibrative transporter to mediate both influx and efflux of nucleosides across the membrane, which is essential for nucleotide synthesis by salvage pathways in cells that lack de novo biosynthetic pathways. In addition, it can also mediate transport of adenine, adenosine, and uridine, as well as several nucleoside analog drugs, such as anticancer and antiviral agents, including cladribine, cordycepin, tubercidin and 3′-azido-3′-deoxythymidine (AZT). SLC29A3 mutations have been linked to a group of heterogeneous hereditary diseases in humans, including H syndrome, Faisalabad histiocytosis, pigmentary hypertrichosis, and non-autoimmune insulin-dependent diabetes mellitus syndromes, and Rosai-Dorfman disease. Unlike other ENT family members with localization on the plasma membrane, SLC29A3 has been reported to be expressed in organelle membranes, including endosomal/lysosomal and mitochondrial membrane.

Fig.1 SLC29A3 deficiency leads to an enlarged and disturbed lysosomal compartment, resulting in accumulation of surplus mitochondria, elevation of intracellular reactive oxygen species, and DNA damage in T cells. (Wei, 2018)

Application SLC29A3 of Membrane Protein in Literature

1. Howaldt A., et al. Sclerosing bone dysplasias with hallmarks of dysosteosclerosis in four patients carrying mutations in SLC29A3 and TCIRG1. Bone. 2019, 120: 495-503. PubMed ID: 30537558
   
   

   This article indicates that SLC29A3 mutations are associated with dysosteosclerosis. In addition, intermediate autosomal recessive osteopetrosis due to TCIRG1 splice site mutations increases the molecular heterogeneity of dysosteosclerosis-like sclerosing bone dysplasias.

2. Wei C.W., et al. Equilibrative Nucleoside Transporter 3 Regulates T Cell Homeostasis by Coordinating Lysosomal Function with Nucleoside Availability. Cell reports. 2018, 23(8): 2330-2341. PubMed ID: 29791845
   
   

   This article reveals that ENT3 functions as a vital metabolite transporter to support T cell homeostasis and activation by regulating lysosomal integrity and the availability of nucleosides.

3. Elwi A.N., et al. Transepithelial fluxes of adenosine and 2′-deoxyadenosine across human renal proximal tubule cells: roles of nucleoside transporters hENT1, hENT2, and hCNT3. American Journal of Physiology-Renal Physiology. 2009, 296(6): F1439-F1451. PubMed ID: 19297449
   
   

   This study finds that apical hCNT3 and basolateral hENT2 are involved in proximal tubular reabsorption of adenosine and some nucleoside drugs. In addition, this article also reveals that apical hENT1 and basolateral hOATs are involved in proximal tubular secretion of 2'-deoxyadenosine.

4. Rahman M.D.F., et al. Identification of structural and molecular features involved in the transport of 3′-deoxynucleoside analogs by human equilibrative nucleoside transporter 3. Drug Metabolism and Disposition. 2018, 46(5): 600-609. PubMed ID: 29530865
   
   

   This article reveals that the N-terminal half of hENT3 is primarily responsible for the hENT3-3'-deoxynucleoside analog interaction and 225D and 231L in the N-terminal half of hENT3 partially contribute to the ability of hENT3 to transport AZT and DDI.

5. Rafiq N.K., et al. Tocilizumab for the Treatment of SLC29A3 Mutation Positive PHID Syndrome. Pediatrics. 2017, 140(5): e20163148. PubMed ID: 29079714
   
   

   This article demonstrates that tocilizumab should be the first choice when considering treatment of the autoinflammatory or cutaneous manifestations of pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID), which is associated with recessive mutations in SLC29A3.

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Reference

1. Wei C W, et al. (2018). Equilibrative Nucleoside Transporter 3 Regulates T Cell Homeostasis by Coordinating Lysosomal Function with Nucleoside Availability. Cell reports. 23(8): 2330-2341.

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