Quality Control of Fungus-specific Glucosylceramide in Cryptococcus neoformans by Endoglycoceramidase-related Protein 1 (EGCrP1)*
Quality Control of Fungus-specific Glucosylceramide in Cryptococcus neoformans by Endoglycoceramidase-related Protein 1 (EGCrP1)*
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DOI：
10.1074/jbc.m111.311340
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发表时间：
2011-11
期刊：
影响因子：
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通讯作者：
Yohei Ishibashi;K. Ikeda;K. Sakaguchi;N. Okino;R. Taguchi;Makoto Ito
中科院分区：
文献类型：
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作者：
Yohei Ishibashi;K. Ikeda;K. Sakaguchi;N. Okino;R. Taguchi;Makoto Ito
背景：由于葡萄糖脑苷脂酶尚未被表征，因此对真菌中 GlcCer 分解代谢知之甚少。结果：EGCrP1 特异性水解 GlcCer，未成熟的 GlcCer 在 EGCrP1 缺陷的新型隐球菌中积累。结论：EGCrP1可消除未成熟的GlcCer，从而控制GlcCer的质量。意义：EGCrP1（第一个在真菌中发现的葡萄糖脑苷脂酶）的发现，为真菌特异性 GlcCer 的质量控制提供了深入的见解。真菌特异性葡萄糖神经酰胺 (GlcCer) 含有独特的鞘氨醇碱基，具有两个双键和一个甲基取代基，对于真菌的致病性至关重要。尽管 GlcCer 的生物合成途径已被很好地阐明，但由于尚未在真菌中鉴定出 GlcCer 降解酶（葡萄糖脑苷脂酶），因此对 GlcCer 分解代谢知之甚少。我们在几个真菌基因组数据库中发现了神经酰胺内切酶的同源物，暂定为神经酰胺内切酶相关蛋白 1 (EGCrP1)。重组EGCrP1水解GlcCer但不水解其他鞘糖脂，而内切糖神经酰胺酶水解寡糖连接的鞘糖脂但不水解GlcCer。新型隐球菌（一种引起隐球菌病的典型病原真菌）中的egcrp1破坏导致真菌特异性GlcCer和未成熟GlcCer的积累，这些未成熟GlcCer具有鞘氨醇碱基而没有甲基取代，同时多糖荚膜形成功能障碍。这些结果表明，EGCrP1 参与 GlcCer 的分解代谢，尤其具有消除体内未成熟 GlcCer 的功能，这些未成熟的 GlcCer 由于 GlcCer 合酶的广泛特异性而作为副产物产生。我们得出的结论是，EGCrP1 是一种首次在真菌中鉴定出的葡萄糖脑苷脂酶，它通过消除新型隐球菌中错误生成的未成熟 GlcCer 来控制 GlcCer 的质量，从而实现真菌特异性 GlcCer 的精确加工。
Background: Little is known about GlcCer catabolism in fungi because glucocerebrosidase has yet to be characterized. Results: EGCrP1 specifically hydrolyzes GlcCer, and immature GlcCer accumulates in EGCrP1-deficient Cryptococcus neoformans. Conclusion: EGCrP1 eliminates immature GlcCer to control the quality of GlcCer. Significance: The finding of EGCrP1, the first glucocerebrosidase identified in fungi, provides insight into the quality control of fungus-specific GlcCer. A fungus-specific glucosylceramide (GlcCer), which contains a unique sphingoid base possessing two double bonds and a methyl substitution, is essential for pathogenicity in fungi. Although the biosynthetic pathway of the GlcCer has been well elucidated, little is known about GlcCer catabolism because a GlcCer-degrading enzyme (glucocerebrosidase) has yet to be identified in fungi. We found a homologue of endoglycoceramidase tentatively designated endoglycoceramidase-related protein 1 (EGCrP1) in several fungal genomic databases. The recombinant EGCrP1 hydrolyzed GlcCer but not other glycosphingolipids, whereas endoglycoceramidase hydrolyzed oligosaccharide-linked glycosphingolipids but not GlcCer. Disruption of egcrp1 in Cryptococcus neoformans, a typical pathogenic fungus causing cryptococcosis, resulted in the accumulation of fungus-specific GlcCer and immature GlcCer that possess sphingoid bases without a methyl substitution concomitant with a dysfunction of polysaccharide capsule formation. These results indicated that EGCrP1 participates in the catabolism of GlcCer and especially functions to eliminate immature GlcCer in vivo that are generated as by-products due to the broad specificity of GlcCer synthase. We conclude that EGCrP1, a glucocerebrosidase identified for the first time in fungi, controls the quality of GlcCer by eliminating immature GlcCer incorrectly generated in C. neoformans, leading to accurate processing of fungus-specific GlcCer.