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.