Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter
Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter
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DOI：
10.1093/jmcb/mjv033
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发表时间：
2016-02-01
影响因子：
5.5
通讯作者：
Vocadlo, David J.
中科院分区：
文献类型：
--
作者：
Zhu, Yanping;Liu, Ta-Wei;Vocadlo, David J.
核孔复合物（NPC）的o -连接n -乙酰氨基葡萄糖（O-GlcNAc）的o -糖基化在后生动物中是保守的。许多包含NPC的核孔蛋白（Nups）构成了o - glcn酰化，但这种修饰的功能作用仍然是谜。我们发现，O-GlcNAc的缺失，由O-GlcNAc转移酶（OGT）的抑制或编码OGT的基因的缺失引起，导致细胞中一些天然的O-GlcNAc酰化的Nups水平下降。O-GlcNAc的缺失会增加这些Nups的泛素化和它们的蛋白酶体降解。这些去糖基化的Nups的半衰期缩短表现为它们从NPC中逐渐消失，以及分裂和有丝分裂后细胞中核孔选择性渗透屏障的下游功能障碍。这些发现确定了O-GlcNAc修饰NPC在维持其组成和选择性过滤器功能方面的关键作用。结果提示鼻咽癌糖基化是鼻咽癌功能的调节因子，并揭示了鼻咽癌保守糖基化在后生动物中的作用。
O-glycosylation of the nuclear pore complex (NPC) by O-linked N-acetylglucosamine (O-GlcNAc) is conserved within metazoans. Many nucleoporins (Nups) comprising the NPC are constitutively O-GlcNAcylated, but the functional role of this modification remains enigmatic. We show that loss of O-GlcNAc, induced by either inhibition of O-GlcNAc transferase (OGT) or deletion of the gene encoding OGT, leads to decreased cellular levels of a number of natively O-GlcNAcylated Nups. Loss of O-GlcNAc enables increased ubiquitination of these Nups and their increased proteasomal degradation. The decreased half-life of these deglycosylated Nups manifests in their gradual loss from the NPC and a downstream malfunction of the nuclear pore selective permeability barrier in both dividing and post-mitotic cells. These findings define a critical role of O-GlcNAc modification of the NPC in maintaining its composition and the function of the selectivity filter. The results implicate NPC glycosylation as a regulator of NPC function and reveal the role of conserved glycosylation of the NPC among metazoans.