The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP.
The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP.
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DOI：
10.1091/mbc.e16-06-0362
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发表时间：
2016-12-15
影响因子：
3.3
通讯作者：
Perng MD
中科院分区：
文献类型：
--
作者：
Lin NH;Huang YS;Opal P;Goldman RD;Messing A;Perng MD
Gigaxonin是一种E3泛素连接酶接头，促进星形胶质细胞中GFAP的蛋白酶体降解。Gigaxonin同样参与了一些但不是所有与疾病相关的GFAP形式的降解。这种降解是由十亿胞囊蛋白与GFAP直接相互作用介导的，并涉及蛋白酶体。亚历山大病（AxD）是星形胶质细胞的原发性遗传疾病，由编码中间丝蛋白GFAP基因的显性突变引起。这种疾病的特征是星形胶质细胞内GFAP（即罗森塔尔纤维）的过度积累。GFAP异常聚集也发生在巨轴突神经病（GAN）中，这是由编码巨轴突蛋白的基因隐性突变引起的。考虑到gigaxonin的功能之一是促进几种IF蛋白的蛋白酶体降解，我们试图确定gigaxonin是否参与GFAP的降解。使用慢病毒转导系统，我们证明了千百亿蛋白水平影响初级星形胶质细胞和表达该IF蛋白的细胞系中GFAP的降解。Gigaxonin同样参与了一些（但不是全部）与axd相关的GFAP突变体的降解。此外，gigaxonin直接与GFAP结合，蛋白酶体的抑制逆转了过表达gigaxonin对细胞中GFAP的清除。这些研究确定了gigaxonin是通过蛋白酶体途径靶向GFAP降解的重要因子。我们的研究结果为未来研究减少或逆转GFAP的病理积累作为AxD和相关疾病的潜在治疗策略提供了重要的基础。
Gigaxonin is an E3 ubiquitin ligase adaptor that facilitates proteasomal degradation of GFAP in astrocytes. Gigaxonin is similarly involved in the degradation of some but not all disease-linked forms of GFAP. This degradation is mediated by a direct interaction of gigaxonin with GFAP and involves the proteasome. Alexander disease (AxD) is a primary genetic disorder of astrocytes caused by dominant mutations in the gene encoding the intermediate filament (IF) protein GFAP. This disease is characterized by excessive accumulation of GFAP, known as Rosenthal fibers, within astrocytes. Abnormal GFAP aggregation also occurs in giant axon neuropathy (GAN), which is caused by recessive mutations in the gene encoding gigaxonin. Given that one of the functions of gigaxonin is to facilitate proteasomal degradation of several IF proteins, we sought to determine whether gigaxonin is involved in the degradation of GFAP. Using a lentiviral transduction system, we demonstrated that gigaxonin levels influence the degradation of GFAP in primary astrocytes and in cell lines that express this IF protein. Gigaxonin was similarly involved in the degradation of some but not all AxD-associated GFAP mutants. In addition, gigaxonin directly bound to GFAP, and inhibition of proteasome reversed the clearance of GFAP in cells achieved by overexpressing gigaxonin. These studies identify gigaxonin as an important factor that targets GFAP for degradation through the proteasome pathway. Our findings provide a critical foundation for future studies aimed at reducing or reversing pathological accumulation of GFAP as a potential therapeutic strategy for AxD and related diseases.