Mechanism underlying the retarded nuclear translocation of androgen receptor splice variants
Mechanism underlying the retarded nuclear translocation of androgen receptor splice variants
复制标题
雄激素受体剪接变体延迟核转位的机制
DOI：
10.1007/s11427-018-9379-x
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发表时间：
2019-02-01
影响因子：
9.1
通讯作者：
Huang, Hefeng
中科院分区：
文献类型：
--
作者：
Liu, Ye;Wang, Yinyu;Huang, Hefeng
如我们先前的研究所示，两种选择性剪接雄激素受体（AR）变体，仅在多囊卵巢综合征患者的颗粒细胞中表达，与野生型AR相比，表现出延迟的核转位。然而，研究人员尚未确定这些异常是否与热休克蛋白90（HSP 90）和输入蛋白α（前者是公认的AR的辅助分子伴侣，后者是经典核输入复合物的组成部分）相关。免疫荧光染色显示，在二氢睾酮（DHT）存在下，这两种变体与HSP 90和importin α主要保留在细胞质中，而在细胞核中的表达水平显著降低。两种AR变体对importin α的结合亲和力持续降低，而在DHT刺激后，WT-AR的结合亲和力增加，导致核输入减少，特别是对插入-AR（Ins-AR）。然而，两种AR变体对HSP 90的结合亲和力在没有DHT的情况下比WT-AR增加，WT-AR的功能是维持空间结构稳定性，特别是对于缺失-AR（Del-AR）。因此，两种AR变异体的核转位延迟与HSP 90和importin α有关，而它们之间的异常结合亲和力在这一过程中起着关键作用。
As shown in our previous study, two alternatively spliced androgen receptor (AR) variants, which are exclusively expressed in the granulosa cells of patients with polycystic ovary syndrome, exhibit retarded nuclear translocation compared with wild-type AR. However, researchers have not yet determined whether these abnormalities correlate with heat shock protein 90 (HSP90) and importin α (the former is a generally accepted co-chaperone of AR, and the latter is a component of classical nuclear import complexes). Here, these two variants were mainly retained in cytoplasm with HSP90 and importin α in the presence of dihydrotestosterone (DHT), and their levels in nucleus were significantly reduced, according to the immunofluorescence staining. The binding affinity of two AR variants for importin α was consistently decreased, while it was increased in WT-AR following DHT stimulation, leading to reduced nuclear import, particularly for the insertion-AR (Ins-AR). However, the binding affinities of two AR variants for HSP90 were increased in the absence of DHT compared with WT-AR, which functioned to maintain spatial structural stability, particularly for the deletion-AR (Del-AR). Therefore, the retarded nuclear translocation of two AR variants is associated with HSP90 and importin α, and the abnormal binding affinities for them play critical roles in this process.