过表达的 Smurf1 在胶质母细胞瘤细胞中通过自噬以 p62 依赖性方式被降解,FEBS Open Bio

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过表达的 Smurf1 在胶质母细胞瘤细胞中通过自噬以 p62 依赖性方式被降解
FEBS Open Bio ( IF 2.8 ) Pub Date : 2021-10-06 , DOI: 10.1002/2211-5463.13310
Da Han ₁ , Shengzhen Li ₁ , Qin Xia ₁ , Xinyi Meng ₁ , Lei Dong ₁

Affiliation

与 E6AP C 末端 (HECT) 型 E3 泛素连接酶 SMAD 特异性 E3 泛素蛋白连接酶 1 (Smurf1) 同源，最初被鉴定为泛素化 TGF-β/BMP 信号通路中的 Smad 蛋白。最近，有报道称Smurf1通过调节多种生物过程来促进肿瘤发生。Smurf1 的高表达通过介导异常细胞信号通路在脑肿瘤进展中发挥着至关重要的作用。此前的报道表明，Smurf1主要通过泛素-蛋白酶体系统降解，但目前尚不清楚Smurf1是否通过肿瘤细胞中的自噬降解。在这项研究中，我们发现自噬激活剂促进胶质母细胞瘤 (GB) 细胞中 Smurf1 的降解。自噬受体 p62 与泛素化底物共定位，促进细胞质货物隔离到自噬体中。我们报告 Smurf1 的自噬降解依赖于 p62。此外，在缺乏 HECT 结构域或 E3 泛素连接酶活性的情况下，Smurf1 的自噬降解会被阻止。我们进一步证明，自噬的激活导致GB细胞中Smurf1的减少以及磷酸肌醇3-激酶/蛋白激酶B信号通路的抑制。我们的结果表明，增强 Smurf1 的自噬降解可能是治疗 GB 的潜在方法。

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Overexpressed Smurf1 is degraded in glioblastoma cells through autophagy in a p62-dependent manner

Homologous to E6AP C-terminus (HECT)-type E3 ubiquitin ligase SMAD-specific E3 ubiquitin protein ligase 1 (Smurf1) was originally identified to ubiquitinate Smad protein in the TGF-β/BMP signaling pathway. Recently, Smurf1 has been reported to promote tumorigenesis by regulating multiple biological processes. High expression of Smurf1 plays a vital role in brain tumor progression by mediating aberrant cell signaling pathways. Previous reports have shown that Smurf1 is degraded mainly through the ubiquitin–proteasome system, but it remains unclear whether Smurf1 is degraded by autophagy in tumor cells. In this study, we show that autophagy activators promote Smurf1 degradation in glioblastoma (GB) cells. The autophagy receptor p62 colocalizes with ubiquitinated substrates to promote sequestration of cytoplasm cargo into the autophagosome. We report that autophagic degradation of Smurf1 is dependent on p62. Moreover, the autophagic degradation of Smurf1 is prevented in the absence of the HECT domain or E3 ubiquitin ligase activity. We further proved that activation of autophagy leads to a decrease of Smurf1 and the inhibition of the phosphoinositide 3-kinase/protein kinase B signaling pathway in GB cells. Our results suggest that enhancement of autophagic degradation of Smurf1 may be a potential approach to treating GB.

更新日期：2021-10-06

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