期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 48, 页码 34384-34393出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.499269
关键词
Drosophila; Fibroblast Growth Factor (FGF); Genetics; Heparan Sulfate; Immunohistochemistry; C5-Epimerase; Gagosome; Sulfation Compensation
资金
- National Institutes of Health [R01 HD042769]
Background: The physiological significance of C5-epimerization of glucuronic acid (GlcA) remains elusive. Results:Drosophila Hsepi mutants are viable and fertile with only minor morphological defects, but they have a short lifespan. Conclusion: Sulfation compensation and 2-O-sulfated GlcA contribute to the mild phenotypes of Hsepi mutants. Significance: The findings suggest novel developmental roles of 2-O-sulfated GlcA. During the biosynthesis of heparan sulfate (HS), glucuronyl C5-epimerase (Hsepi) catalyzes C5-epimerization of glucuronic acid (GlcA), converting it to iduronic acid (IdoA). Because HS 2-O-sulfotransferase (Hs2st) shows a strong substrate preference for IdoA over GlcA, C5-epimerization is required for normal HS sulfation. However, the physiological significance of C5-epimerization remains elusive. To understand the role of Hsepi in development, we isolated Drosophila Hsepi mutants. Homozygous mutants are viable and fertile with only minor morphological defects, including the formation of an ectopic crossvein in the wing, but they have a short lifespan. We propose that two mechanisms contribute to the mild phenotypes of Hsepi mutants: HS sulfation compensation and possible developmental roles of 2-O-sulfated GlcA (GlcA2S). HS disaccharide analysis showed that loss of Hsepi resulted in a significant impairment of 2-O-sulfation and induced compensatory increases in N- and 6-O-sulfation. Simultaneous block of Hsepi and HS 6-O-sulfotransferase (Hs6st) activity disrupted tracheoblast formation, a well established FGF-dependent process. This result suggests that the increase in 6-O-sulfation in Hsepi mutants is critical for the rescue of FGF signaling. We also found that the ectopic crossvein phenotype can be induced by expression of a mutant form of Hs2st with a strong substrate preference for GlcA-containing units, suggesting that this phenotype is associated with abnormal GlcA 2-O-sulfation. Finally, we show that Hsepi formed a complex with Hs2st and Hs6st in S2 cells, raising the possibility that this complex formation contributes to the close functional relationships between these enzymes.
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