Abstract
Heparan sulfate endosulfatases Sulf1 and Sulf2 hydrolyze 6-O-sulfate in heparan sulfate, thereby regulating cellular signaling. Previous studies have revealed that Sulfs act predominantly on UA2S-GlcNS6S disaccharides and weakly on UA-GlcNS6S disaccharides. However, the specificity of Sulfs and their role in sulfation patterning of heparan sulfate in vivo remained unknown. Here, we performed disaccharide analysis of heparan sulfate in Sulf1 and Sulf2 knock-out mice. Significant increases in ΔUA2S-GlcNS6S were observed in the brain, small intestine, lung, spleen, testis, and skeletal muscle of adult Sulf1(-/-) mice and in the brain, liver, kidney, spleen, and testis of adult Sulf2(-/-) mice. In addition, increases in ΔUA-GlcNS6S were seen in the Sulf1(-/-) lung and small intestine. In contrast, the disaccharide compositions of chondroitin sulfate were not primarily altered, indicating specificity of Sulfs for heparan sulfate. For Sulf1, but not for Sulf2, mRNA expression levels in eight organs of wild-type mice were highly correlated with increases in ΔUA2S-GlcNS6S in the corresponding organs of knock-out mice. Moreover, overall changes in heparan sulfate compositions were greater in Sulf1(-/-) mice than in Sulf2(-/-) mice despite lower levels of Sulf1 mRNA expression, suggesting predominant roles of Sulf1 in heparan sulfate desulfation and distinct regulation of Sulf activities in vivo. Sulf1 and Sulf2 mRNAs were differentially expressed in restricted types of cells in organs, and consequently, the sulfation patterns of heparan sulfate were locally and distinctly altered in Sulf1 and Sulf2 knock-out mice. These findings indicate that Sulf1 and Sulf2 differentially contribute to the generation of organ-specific sulfation patterns of heparan sulfate.
Highlights
Extracellular endosulfatases sulfatase 1 (Sulf1) and sulfatase 2 (Sulf2) hydrolyze 6-O-sulfate in heparan sulfate
Sulfate were locally and distinctly altered in Sulf1 and Sulf2 knock-out mice. These findings indicate that Sulf1 and Sulf2 differentially contribute to the generation of organ-specific sulfation patterns of heparan sulfate
The compositions of the eight unsaturated disaccharides were compared with the unsaturated Heparan sulfate (HS) disaccharide standards and quantitatively determined. 3-O-Sulfated disaccharide units were not detected because they were resistant to heparin lyase digestion
Summary
Extracellular endosulfatases Sulf and Sulf hydrolyze 6-O-sulfate in heparan sulfate. Results: Disaccharide analysis showed that 2-O-, 6-O-, and N-trisulfated disaccharide units in heparan sulfate were increased to different degrees in different organs in Sulf and Sulf knock-out mice. The specificity of Sulfs and their role in sulfation patterning of heparan sulfate in vivo remained unknown. Overall changes in heparan sulfate compositions were greater in Sulf1؊/؊ mice than in Sulf2؊/؊ mice despite lower levels of Sulf mRNA expression, suggesting predominant roles of Sulf in heparan sulfate desulfation and distinct regulation of Sulf activities in vivo. Sulf and Sulf mRNAs were differentially expressed in restricted types of cells in organs, and the sulfation patterns of heparan. Sulfate were locally and distinctly altered in Sulf and Sulf knock-out mice These findings indicate that Sulf and Sulf differentially contribute to the generation of organ-specific sulfation patterns of heparan sulfate. Our data provide evidence that Sulf and Sulf contribute differentially to the generation of organ-specific sulfation patterns of HS in vivo
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