The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules

Abstract

Platelet dense granules are lysosomerelated organelles which contain high concentrations of several biologically important low-molecular-weight molecules. These include calcium, serotonin, adenine nucleotides, pyrophosphate, and polyphosphate, which are necessary for normal blood hemostasis. The synthesis of dense granules and other lysosomerelated organelles is defective in inherited diseases such as Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS). HPS and CHS mutations in 8 human and at least 16 murine genes have been identified. Previous studies produced contradictory findings for the function of the murine ashen (Rab27a) gene in platelet-dense granules. We have used a positional cloning approach with one line of ashen mutants to establish that a new mutation in a second gene, Slc35d3, on mouse chromosome 10 is the basis of this discrepancy. IntroductionPlatelet activation induces secretion of the contents of several subcellular organelles, including ␣ granules, lysosomes, and dense granules. 1,2 ␣ Granules contain multiple proteins critical to adhesion and repair such as von Willebrand factor, thrombospondin, and fibrinogen. Lysosomes hold a battery of hydrolytic enzymes postulated to function in elimination of circulating platelet aggregates. Dense granules like lysosomes are acidic organelles but, unlike the aforementioned organelles, contain extremely high concentrations of small nonprotein components, including calcium, serotonin, adenine nucleotides, and pyrophosphate, which are thought to exist as an insoluble complex within platelets. 2 They are among the first components released from activated platelets and participate in clotting in numerous ways. For example, serotonin causes vasoconstriction. ADP activates and recruits nearby platelets. More recently, high concentrations of polyphosphate were found within platelet-dense granules. 3 Platelet-derived polyphosphate is a potent modulator of blood coagulation and fibrinolysis. 4 The biosynthesis of platelet dense and ␣ granules is thought to proceed through a common multivesicular body intermediate. 5 A wide variety of genes causative for the inherited diseases, Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS), regulate the biosynthesis of dense granules, probably through control of vesicle trafficking. Platelet dense granules are absent or greatly reduced in a number in these diseases, and/or dense granule contents are significantly lower, leaving "empty" organelles. HPS is a genetically heterogeneous disease affecting the biosynthesis and/or intracellular transport of lysosome-related organelles (LROs) and their precursor vesicles. 6-10 LROs commonly affected include melanosomes, platelet-dense granules, and lamellar bodies of lung type II cells. Clinical presentation includes oculocutaneous albinism and lowered visual acuity, prolonged bleeding and, in many cases, early death from fibrotic lung disease. There is presently no permanent treatment for HPS, although bone marrow transplantation has restored normal p...

Molecular cloning, sequence characteristics, and tissue expression analysis of the SLC35D3 gene in lean, obese and mini-type pigs

“…However, it was more highly expressed in adipose tissues compared to other tissues, including heart, liver, and kidney. In the mouse, SLC35D3 is primarily expressed in the liver and kidney compared with other organs, but not in adipose tissues [20]. Based on our results, we conclude that SLC35D3 may have an important function in adipose tissue.…”

“…A recent study found that obesity is not only caused by abnormal metabolism, Li Wei research group found that the SLC35D3 protein was participate in fat deposition, meanwhile it is involved in the neural regulation process, and this is the first report about metabolic disorder caused by unusual central behavior not due to endocrine disorders. SLC35D3 localizes on mouse chromosome 10 and regulates platelet-dense granule content [20]. In the human, the SLC35D3 gene, which localizes on chromosome 6 close to the D6S1009, its mutation can cause obesity, it is a candidate gene for MetS [19].…”

“…Liwei group found it close to human 6 chromosome long arm D6S1009 sites, and to be thought as a candidate gene for MetS, which is involved in metabolic control in the central nervous system by regulating dopamine signaling [16][17][18][19]. Recent research indicates that SLC35D3 is involved in the biogenesis of platelet dense granules, and the expression of SLC35D3 in the brain was limited to expressing D1R rather than D2R [20][21][22]. Other results suggest that SLC35D3 is a new regulator of tissue-specific autophagy and plays an important role in the increased autophagic activity required for the survival of subsets of DA neurons [23].…”

SLC35D3 increases autophagic activity in midbrain dopaminergic neurons by enhancing BECN1-ATG14-PIK3C3 complex formation

“…It has been reported that SLC35D3 is involved in the biogenesis of platelet dense granules. 20,21 Moreover, Slc35d3 is specifically expressed in the substantia nigra (SN), striatum, and olfactory bulb in mouse brain. 22 It functions as an ER chaperone for DRD1 (dopamine receptor D1) trafficking to the plasma membrane of the medium spiny neurons in the striatum.…”

“…20 SLC35D3 is predicted to be an orphan nucleotide sugar transporter or a fringe connection-like protein with 10 transmembrane domains. It has been reported that SLC35D3 is involved in the biogenesis of platelet dense granules.…”