The ubiquitin ligase Smad ubiquitination regulatory factor 1 (Smurf1) targets many proteins including Smad1/5 for ubiquitin-dependent proteasomal degradation. However, how Smurf1 is degraded remains unclear. Here we show that REG gamma, an activator for the 20S proteasome-mediated protein degradation, interacts with Smurf1 and mediates its degradation. We provide evidence that depletion of REG gamma stabilizes Smurf1 whereas overexpression of REG gamma promotes the degradation of Smurf1. Interestingly both Smurf2 and Smurf1 are destabilized by the REG gamma proteasome while the other members of Neural precursor cell-expressed developmentally downregulated gene 4 family were not affected. More importantly, we found that the REG gamma proteasome-mediated degradation of Smurf1 results in degradation of Smad5. These findings reveal that the REG gamma-proteasome targets a ubiquitin ligase for protein degradation. Structured summary: MINT-7894509: CKIP (uniprotkb:Q53GL0) binds (MI:0407) to Smurf1 (uniprotkb:Q9HCE7) by pull down (MI:0096) MINT-7894494: REG gamma (uniprotkb:P61289) binds (MI:0407) to Smurf1 (uniprotkb:Q9HCE7) by pull down (MI:0096) MINT-7894523, MINT-7894543, MINT-7894481: REG gamma (uniprotkb:P61289) physically interacts (MI:0915) with Smurf1 (uniprotkb:Q9HCE7) by anti tag coimmunoprecipitation (MI:0007) MINT-7894558: Smurf1 (uniprotkb:Q9HCE7) physically interacts (MI:0915) with REG gamma (uniprotkb: P61289) by two hybrid (MI:0018) (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.