PIAS1 介导的 SUMO3 修饰调节雄激素受体的细胞分布和稳定性。
SUMO3 modification by PIAS1 modulates androgen receptor cellular distribution and stability.
机构信息
The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, Northeast Normal University, 5268 People's Street, Changchun, Jilin, 130024, People's Republic of China.
Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Cytology and Genetics, Hengyang School of Medicine, University of South China, Hengyang, Hunan, 421001, People's Republic of China.
出版信息
Cell Commun Signal. 2019 Nov 21;17(1):153. doi: 10.1186/s12964-019-0457-9.
BACKGROUND
Abnormal reactivation of androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) mainly results from overexpression and down-regulation of AR. Sumoylation of AR can influence its function. However, regulation of AR sumoylation by SUMO E3 ligases PIASs to modify AR distribution and stability are not well understood.
METHODS
We assessed the potential effect of SUMO3 modification on AR intracellular localization by immunostaining in AR-negative prostate cancer DU145 cells, and detected the effect of PIAS1/SUMO3 overexpression on AR sumoylation related degradation. Then we characterized AR sumoylation sites involved modified by SUMO3, and the key residue of PIAS1 involved in itself sumoylation and further mediated AR sumoylation (sumo3-conjugated), translocation and degradation. Finally we detected the recognition of PIAS1 (sumoylation ligase) to MDM2, a ubiquin ligase mediated AR degradation.
RESULTS
We demonstrate that SUMO E3 ligase PIAS1, along with SUMO3, mediates AR cytosolic translocation and subsequent degradation via a ubiquitin-proteasome pathway. Although AR sumoylation occurs prior to ubiquitination, the SUMO-acceptor lysine 386 on AR, together with ubiquitin-acceptor lysine 845, contribute to PIAS1/SUMO3-induced AR nuclear export, ubiquitination and subsequent degradation. Moreover, PIAS1 itself is modified by SUMO3 overexpression, and mutation of SUMO-acceptor lysine 117 on PIAS1 can impair AR cytoplasmic distribution, demonstrating the essential role of sumoylated PIAS1 in AR translocation. We further determine that sumoylated PIAS1 interacts with AR lysine 386 and 845 to form a binary complex. Consistent with the effect on AR distribution, SUMO3 modification of PIAS1 is also required for AR ubiquitination and degradation by recruiting ubiquitin E3 ligase MDM2.
CONCLUSION
Taken together, SUMO3 modification of PIAS1 modulates AR cellular distribution and stability. Our study provided the evidence the crosstalk between AR sumoylation and ubquitination mediated by PIAS1 and SUMO3.
背景
雄激素受体（AR）信号在去势抵抗性前列腺癌（CRPC）中的异常激活主要是由于 AR 的过度表达和下调。AR 的 SUMO 化可以影响其功能。然而，SUMO E3 连接酶 PIASs 对 AR SUMO 化的调节，以改变 AR 的分布和稳定性，尚不清楚。
方法
我们通过免疫染色评估 SUMO3 修饰对 AR 阴性前列腺癌细胞 DU145 中 AR 细胞内定位的潜在影响，并检测 PIAS1/SUMO3 过表达对 AR SUMO 化相关降解的影响。然后，我们描述了涉及 SUMO3 修饰的 AR SUMO 化位点，以及 PIAS1 中参与自身 SUMO 化和进一步介导 AR SUMO 化（SUMO3 缀合）、易位和降解的关键残基。最后，我们检测了 PIAS1（SUMO 连接酶）对 MDM2 的识别，MDM2 是一种泛素连接酶介导的 AR 降解。
结果
我们证明 SUMO E3 连接酶 PIAS1 与 SUMO3 一起通过泛素蛋白酶体途径介导 AR 细胞质易位和随后的降解。虽然 AR SUMO 化发生在泛素化之前，但 AR 上的 SUMO 受体赖氨酸 386 与泛素受体赖氨酸 845 一起，有助于 PIAS1/SUMO3 诱导的 AR 核输出、泛素化和随后的降解。此外，PIAS1 自身被 SUMO3 过表达修饰，PIAS1 上 SUMO 受体赖氨酸 117 的突变可以损害 AR 细胞质分布，证明了 SUMO 化的 PIAS1 在 AR 易位中的重要作用。我们进一步确定，SUMO 化的 PIAS1 与 AR 的赖氨酸 386 和 845 相互作用形成二元复合物。与 AR 分布的影响一致，SUMO3 修饰的 PIAS1 还通过招募泛素 E3 连接酶 MDM2 来促进 AR 泛素化和降解。
结论
总之，PIAS1 的 SUMO3 修饰调节 AR 的细胞内分布和稳定性。我们的研究提供了证据表明，PIAS1 和 SUMO3 介导的 AR SUMO 化和泛素化之间存在串扰。
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