Lowered Expression of Heparan Sulfate/Heparin Biosynthesis Enzyme N-Deacetylase/N-Sulfotransferase 1 Results in Increased Sulfation of Mast Cell Heparin
Lowered Expression of Heparan Sulfate/Heparin Biosynthesis Enzyme N-Deacetylase/N-Sulfotransferase 1 Results in Increased Sulfation of Mast Cell Heparin
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DOI：
10.1074/jbc.m111.303891
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发表时间：
2011-12-30
影响因子：
4.8
通讯作者：
Abrink, Magnus
中科院分区：
文献类型：
--
作者：
Dagalv, Anders;Holmborn, Katarina;Abrink, Magnus
硫酸乙酰肝素生物合成酶N-脱乙酰基酶/N-磺基转移酶1（NDST 1）在小鼠中的缺乏会导致所有器官中硫酸乙酰肝素生物合成的严重干扰，而NDST 2的缺乏仅影响肥大细胞（MC）中的肝素生物合成。为了研究NDST 1和NDST 2在MC发育过程中的单独和组合作用，分别对来自小鼠胚胎和胚胎干细胞的体外分化MC进行了研究。而MC的发展不会发生在NDST 1和NDST 2的情况下，缺乏NDST 2单独的结果在缺陷MC的产生。令人惊讶的是，NDST 1（+/-）和NDST 1（-/-）MC中产生的肝素的相对量（约30%）高于对照MC，其中产生的约95%的S-35标记的糖胺聚糖是硫酸软骨素。NDST 1的表达降低还导致合成的肝素的硫酸盐含量更高，并伴随着储存的MC蛋白酶水平的增加。一个模型的GAGosome，一个假设的高尔基体酶复合物，是用来解释的结果。
Deficiency of the heparan sulfate biosynthesis enzyme N-deacetylase/N-sulfotransferase 1 (NDST1) in mice causes severely disturbed heparan sulfate biosynthesis in all organs, whereas lack of NDST2 only affects heparin biosynthesis in mast cells (MCs). To investigate the individual and combined roles of NDST1 and NDST2 during MC development, in vitro differentiated MCs derived from mouse embryos and embryonic stem cells, respectively, have been studied. Whereas MC development will not occur in the absence of both NDST1 and NDST2, lack of NDST2 alone results in the generation of defective MCs. Surprisingly, the relative amount of heparin produced in NDST1(+/-) and NDST1(-/-) MCs is higher (approximate to 30%) than in control MCs where approximate to 95% of the S-35-labeled glycosaminoglycans produced is chondroitin sulfate. Lowered expression of NDST1 also results in a higher sulfate content of the heparin synthesized and is accompanied by increased levels of stored MC proteases. A model of the GAGosome, a hypothetical Golgi enzyme complex, is used to explain the results.