nucleoside transporters
Plasma membrane transport of nucleosides is mediated by equilibrative and concentrative nucleoside transporters, which may have specificity for purines or pyrimidines.
Nucleoside transport in mammalian cells is performed by two types of transporters. The SLC28s family is responsible for active, sodium-dependent nucleoside transport mainly in specialised cells. In contrast the SLC29s protein family (also known as equilibrative nucleoside transporters) are passive transporters and have a wide tissue distribution.
While hENT4 functions as an organic cation transporter with minimal interaction with nucleosides or nucleoside analogues, hENT1, hENT2 and hENT3 have been implicated in nucleoside transport and hENT3 has been reported to be a broad selectivity, low affinity nucleoside transporter that can transport adenine.
hENT3 was also reported to be a pH-dependent intracellular transporter with partial localization to late endosomes/lysosomes (the hENT1, 2 and 4 localise to the plasma membrane) and to contain a (DE)XXXL(LI) endosomal/lysosomal targeting motif.
However, it was reported that endogenous hENT3 mainly localises to the mitochondria and is predominantly a mitochondrial transporter.
Although germline mutations in genes encoding the mitochondrial enzymes succinate dehydrogenase and fumarate hydratase are associated with neoplasia, these disorders do not show phenotypic overlap with FHC/fRDD.
hENT3 has a similar broad permeant selectivity for nucleosides and nucleobases and the availability of a cytoplasmic pool of nucleosides is a key requirement for several cellular processes including the nucleoside salvage pathway and the generation of ATP/GTP for energy metabolism and signal transduction pathways.
In view of two early onset cancers in a proband with FHC we wondered whether SLC29A3 might predispose to neoplasia (e.g. by altering adenosine metabolism as extracellular adenosine has been reported to induce apoptosis and proliferation in gastric, leukaemia and hepatic cancer cell lines).
Ectopic expression of SLC29A3 suppressed cell growth in vitro but did not find conclusive evidence of SLC29A3 inactivation in breast or bladder cancers.
Further clinical studies are required to determine whether the frequency of neoplasia in SLC29A3 spectrum disorder is increased or whether the findings in the FHC family are coincidental.
Kknockdown of the Drosophila orthologue of SLC29A3 (dENT1) results in a variety of phenotypes ranging from lethality in pupal and pharate adult stages (with complete knockdown) or adult flies with abnormal sensory bristle development (mild knockdown).
The latter phenotype has been linked to abnormalities of insulin signalling pathway, and, in contrast to the growth suppressive effects of hENT3 in human cell line, dENT1 appeared to be a positive promoter of cell size or number.
The identification of genes for rare familial syndromes can provide insights into the molecular pathogenesis of more common disorders. Hence the analysis of the SLC29A3 pathway in sporadic Rosai-Dorfman disease, will be of interest.
Members
| SLC5s | SLC5A1 | |||
| SLC28s | SLC28A1 | SLC28A2 | ||
| SLC29s | SLC29A1 | SLC29A2 | SLC29A3 |
See also:
nucleosides
nucleoside transport