A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome
A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome
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DOI：
10.1242/jcs.083287
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发表时间：
2011-08-15
影响因子：
4
通讯作者：
Hanover, John A.
中科院分区：
文献类型：
--
作者：
Keembiyehetty, Chithra N.;Krzeslak, Anna;Hanover, John A.
蛋白质-O-连接的N-乙酰基-β-D-氨基葡萄糖苷酶（O-GlcNAc酶，OGA;也称为氨基己糖苷酶C）通过从关键靶蛋白中去除O-连接的N-乙酰基氨基葡萄糖（O-GlcNAc）参与营养物感应、氨基己糖信号传导途径。O-GlcNAc信号传导的紊乱与阿尔茨海默病、糖尿病和癌症有关。哺乳动物O-GlcNAc酶以两种主要的剪接同种型存在，区别仅在于存在（OGA-L）或不存在（OGA-S）组蛋白乙酰转移酶结构域。在这里，我们表明，OGA-S积累在新生的脂滴与perilipin-2的表面上，这两种蛋白质是稳定的蛋白酶体抑制。我们发现，选择性下调OGA-S的结果在全球蛋白酶体抑制和泛素化蛋白的显着积累。OGA-S敲除增加了围脂蛋白-2和围脂蛋白-3的水平，表明O-GlcNAc依赖性的蛋白酶体调节可能发生在脂滴表面。通过在新生脂滴成熟期间局部激活蛋白酶体，OGA-S可以参与调节脂滴表面重塑的O-GlcNAc依赖性反馈环。因此，我们的研究结果表明，己糖胺信号和脂滴组装和动员之间的机械联系。
Protein-O-linked N-Acetyl-beta-D-glucosaminidase (O-GlcNAcase, OGA; also known as hexosaminidase C) participates in a nutrient-sensing, hexosamine signaling pathway by removing O-linked N-acetylglucosamine (O-GlcNAc) from key target proteins. Perturbations in O-GlcNAc signaling have been linked to Alzheimer's disease, diabetes and cancer. Mammalian O-GlcNAcase exists as two major spliced isoforms differing only by the presence (OGA-L) or absence (OGA-S) of a histone-acetyltransferase domain. Here we demonstrate that OGA-S accumulates on the surface of nascent lipid droplets with perilipin-2; both of these proteins are stabilized by proteasome inhibition. We show that selective downregulation of OGA-S results in global proteasome inhibition and the striking accumulation of ubiquitinylated proteins. OGA-S knockdown increased levels of perilipin-2 and perilipin-3 suggesting that O-GlcNAc-dependent regulation of proteasomes might occur on the surface of lipid droplets. By locally activating proteasomes during maturation of the nascent lipid droplet, OGA-S could participate in an O-GlcNAc-dependent feedback loop regulating lipid droplet surface remodeling. Our findings therefore suggest a mechanistic link between hexosamine signaling and lipid droplet assembly and mobilization.