Vimentin is a ubiquitination and degradation substrate of the ubiquitin ligase KPC1

The ubiquitin proteasome system (UPS), driven by ubiquitin as a degradation signal, eliminates, in a highly specific manner, 'abnormal' proteins and proteins that completed their function. This process involves a hierarchical cascade of E1, E2, and E3 enzymes. The E3 ubiquitin ligases, act as specific receptors that bind their cognate substrates. We have previously shown that the ubiquitin ligase KPC1 possesses a strong tumor-suppressive characteristic caused by the p50 subunit of the NF-κB transcription factor, which is generated by limited, KPC1-mediated processing of its p105 precursor. In this study, we identified vimentin as a novel substrate of the KPC1. We demonstrated that the ligase forms a complex with vimentin and modifies it by ubiquitination. Overexpression of KPC1 in HEK293T cells downregulates vimentin expression. Conversely, deletion of KPC1 in HAP1 cells results in upregulation of vimentin. Importantly, we revealed both in vitro and in a tumor model in mice that at least part of this effect is mediated through the downregulation of vimentin. Furthermore, in human clear cell renal cell carcinoma (ccRCC) samples, we found a negative correlation between KPC1 and vimentin expression. Overall, we demonstrate that the KPC1 ubiquitin E3 ligase downregulates vimentin expression, thereby reducing migration and tumorigenicity of cancer cells.