QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling.
QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling.
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DOI：
10.1083/jcb.200212083
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发表时间：
2003-07-21
影响因子：
7.8
通讯作者：
Emerson, Charles P Jr
中科院分区：
文献类型：
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作者：
Ai, Xingbin;Do, Anh-Tri;Lozynska, Olga;Kusche-Gullberg, Marion;Lindahl, Ulf;Emerson, Charles P Jr
细胞表面硫酸乙酰肝素蛋白聚糖（HSPGs）的6-O硫酸化状态被动态调节以控制胚胎祖细胞谱系的生长和特化。然而，HSPG硫酸化的调节机制尚不清楚。在这里，我们报告QSulf 1，一种新的细胞表面硫酸酯酶的生物化学和Wnt信号转导活动。生物化学研究证实，QSulf 1是硫酸乙酰肝素（HS）6-O内切硫酸酯酶，特别是HS链内的三硫酸化IdoA 2S-GlcNS 6S二糖单元。在细胞中，QSulf 1定位于细胞表面或高尔基体中时，可以自主地发挥细胞功能以重塑细胞表面HS的硫酸化并促进Wnt信号传导。QSulf 1 6-O取代减少XWnt与肝素和Glypican 1的HS链的结合，而肝素以高亲和力与XWnt 8结合并抑制Wnt信号传导。HS生物合成的CHO细胞突变体在Wnt依赖性Frizzled受体活化方面有缺陷，这表明HS是Frizzled受体功能所需的。总之，这些研究结果表明，一个两个状态的“捕获或呈现”模型QSulf 1的Wnt信号的调节，其中QSulf 1删除6-O硫酸根从HS链，以促进低亲和力HS-Wnt复合物的形成，可以功能性地与卷曲受体相互作用，启动Wnt信号转导。
The 6-O sulfation states of cell surface heparan sulfate proteoglycans (HSPGs) are dynamically regulated to control the growth and specification of embryonic progenitor lineages. However, mechanisms for regulation of HSPG sulfation have been unknown. Here, we report on the biochemical and Wnt signaling activities of QSulf1, a novel cell surface sulfatase. Biochemical studies establish that QSulf1 is a heparan sulfate (HS) 6-O endosulfatase with preference, in particular, toward trisulfated IdoA2S-GlcNS6S disaccharide units within HS chains. In cells, QSulf1 can function cell autonomously to remodel the sulfation of cell surface HS and promote Wnt signaling when localized either on the cell surface or in the Golgi apparatus. QSulf1 6-O desulfation reduces XWnt binding to heparin and HS chains of Glypican1, whereas heparin binds with high affinity to XWnt8 and inhibits Wnt signaling. CHO cells mutant for HS biosynthesis are defective in Wnt-dependent Frizzled receptor activation, establishing that HS is required for Frizzled receptor function. Together, these findings suggest a two-state “catch or present” model for QSulf1 regulation of Wnt signaling in which QSulf1 removes 6-O sulfates from HS chains to promote the formation of low affinity HS–Wnt complexes that can functionally interact with Frizzled receptors to initiate Wnt signal transduction.