Arylsulfatase G inactivation causes loss of heparan sulfate 3-O-sulfatase activity and mucopolysaccharidosis in mice
Arylsulfatase G inactivation causes loss of heparan sulfate 3-O-sulfatase activity and mucopolysaccharidosis in mice
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DOI：
10.1073/pnas.1202071109
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发表时间：
2012-06-26
影响因子：
11.1
通讯作者：
Dierks, Thomas
中科院分区：
文献类型：
--
作者：
Kowalewski, Bjoern;Lamanna, William C.;Dierks, Thomas
糖胺聚糖（GAG）降解缺陷导致溶酶体储存障碍的一个亚类，称为粘多糖病（mps），其中许多表现为严重的神经病理学。在GAG硫酸肝素降解的关键步骤仍然是谜。本研究表明，溶酶体芳基硫酸酯酶G （ARSG）是长期寻找的完成硫酸肝素降解所需的氨基-3- o -硫酸酯酶。硫酸肝素缺乏小鼠在内脏器官和中枢神经系统中积累硫酸肝素，并发生神经元细胞死亡和行为缺陷。这种积累的硫酸乙酰肝素表现出独特的非还原末端结构，末端有n -磺基氨基-3- o -硫酸盐残基，可以诊断这种疾病。重组人ARSG能够从这些残基中切割3- o -硫酸盐基团，以及从真正的3- o -硫酸盐n -磺基氨基葡萄糖标准中切割。我们的研究结果证明了ARSG在硫酸肝素降解中的关键作用，并强烈表明ARSG缺乏代表了一种独特的，迄今未知的MPS形式，我们称之为MPS IIIE。
Deficiency of glycosaminoglycan (GAG) degradation causes a subclass of lysosomal storage disorders called mucopolysaccharidoses (MPSs), manyof which present with severe neuropathology. Critical steps in the degradation of the GAG heparan sulfate remain enigmatic. Here we show that the lysosomal arylsulfatase G (ARSG) is the long-sought glucosamine-3-O-sulfatase required to complete the degradation of heparan sulfate. Arsg-deficient mice accumulate heparan sulfate in visceral organs and the central nervous system and develop neuronal cell death and behavioral deficits. This accumulated heparan sulfate exhibits unique nonreducing end structures with terminal N-sulfoglucosamine-3-O-sulfate residues, allowing diagnosis of the disorder. Recombinant human ARSG is able to cleave 3-O-sulfate groups from these residues as well as from an authentic 3-O-sulfated N-sulfoglucosamine standard. Our results demonstrate the key role of ARSG in heparan sulfate degradation and strongly suggest that ARSG deficiency represents a unique, as yet unknown form of MPS, which we term MPS IIIE.