Loss of the N-acetylgalactosamine side chain of the GPI-anchor impairs bone formation and brain functions and accelerates the prion disease pathology.
Loss of the N-acetylgalactosamine side chain of the GPI-anchor impairs bone formation and brain functions and accelerates the prion disease pathology.
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DOI：
10.1016/j.jbc.2022.101720
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Kinoshita T
中科院分区：
文献类型：
--
作者：
Hirata T;Kobayashi A;Furuse T;Yamada I;Tamura M;Tomita H;Tokoro Y;Ninomiya A;Fujihara Y;Ikawa M;Maeda Y;Murakami Y;Kizuka Y;Kinoshita T
糖基磷脂酰肌醇（GPI）是蛋白质的翻译后糖脂修饰，其将蛋白质锚定在细胞表面的脂筏中。虽然一些GPI锚定蛋白（GPI-AP），包括朊病毒蛋白PrPC，在GPI糖脂的核心结构上具有由N-乙酰半乳糖胺（GalNAc）−半乳糖−唾液酸组成的聚糖侧链，但该GPI-GalNAc侧链的体内功能在很大程度上尚未解决。在这里，我们研究了GPI-GalNAc侧链在体内的生理和病理作用，通过敲除其起始酶，PGAP 4，在小鼠中。我们表明，Pgap 4 mRNA在大脑中，特别是在神经元中高度表达，质谱分析证实了PGAP 4-KO小鼠大脑中PrPC GPI中GalNAc侧链的丢失。此外，PGAP 4-KO小鼠表现出各种表型，包括血液碱性磷酸酶水平升高、骨形成受损、自发活动减少和记忆受损，尽管各种GPI-AP的表达水平和脂筏缔合正常。因此，我们得出结论，GPI-GalNAc侧链是必需的GPI-AP在哺乳动物体内的功能，特别是在骨骼和大脑。此外，PGAP 4-KO小鼠更容易感染朊病毒疾病，并且在脑内接种致病性朊病毒株后比野生型小鼠更早死亡，突出了GalNAc侧链对朊病毒疾病的保护作用。
Glycosylphosphatidylinositol (GPI) is a posttranslational glycolipid modification of proteins that anchors proteins in lipid rafts on the cell surface. Although some GPI-anchored proteins (GPI-APs), including the prion protein PrPC, have a glycan side chain composed of N-acetylgalactosamine (GalNAc)−galactose−sialic acid on the core structure of GPI glycolipid, in vivo functions of this GPI-GalNAc side chain are largely unresolved. Here, we investigated the physiological and pathological roles of the GPI-GalNAc side chain in vivo by knocking out its initiation enzyme, PGAP4, in mice. We show that Pgap4 mRNA is highly expressed in the brain, particularly in neurons, and mass spectrometry analysis confirmed the loss of the GalNAc side chain in PrPC GPI in PGAP4-KO mouse brains. Furthermore, PGAP4-KO mice exhibited various phenotypes, including an elevated blood alkaline phosphatase level, impaired bone formation, decreased locomotor activity, and impaired memory, despite normal expression levels and lipid raft association of various GPI-APs. Thus, we conclude that the GPI-GalNAc side chain is required for in vivo functions of GPI-APs in mammals, especially in bone and the brain. Moreover, PGAP4-KO mice were more vulnerable to prion diseases and died earlier after intracerebral inoculation of the pathogenic prion strains than wildtype mice, highlighting the protective roles of the GalNAc side chain against prion diseases.
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影响因子：
4.8
作者：
BREWIS, IA;FERGUSON, MAJ;HOOPER, NM
通讯作者：
HOOPER, NM
影响因子：
2.7
作者：
Grathwohl, KUD;Horiuchi, M;Shinagawa, M
通讯作者：
Shinagawa, M
影响因子：
6.7
作者：
Chesebro B;Race B;Meade-White K;Lacasse R;Race R;Klingeborn M;Striebel J;Dorward D;McGovern G;Jeffrey M
通讯作者：
Jeffrey M
在催化结构域中用串联跨膜区域的高尔基GPI GPI-N-乙酰乳糖苷转移酶的鉴定。
影响因子：
16.6
作者：
Hirata T;Mishra SK;Nakamura S;Saito K;Motooka D;Takada Y;Kanzawa N;Murakami Y;Maeda Y;Fujita M;Yamaguchi Y;Kinoshita T
通讯作者：
Kinoshita T
DOI：
10.1073/pnas.142063399
发表时间：
2002-07-09
影响因子：
11.1
作者：
Hessle, L;Johnson, KA;Millán, JL
通讯作者：
Millán, JL