Inhibition of the deubiquitinase USP5 leads to c-Maf protein degradation and myeloma cell apoptosis

• DOI: 10.1038/cddis.2017.450
• Publication Date: 2017-09-21T12:40:59Z
• Authors: Siyu Wang; Jiaxiang Juan; Zubin Zhang; Yanyun Du; Yujia Xu; Jiefei Tong; Biyin Cao; Michael F Moran; Yuanying Zeng; Xinliang Mao
• Keywords: Deubiquitinating enzyme

Abstract The deubiquitinase USP5 stabilizes c-Maf, a key transcription factor in multiple myeloma (MM), but the mechanisms and significance are unclear. In present study, was found to interact with c-Maf prevented it from degradation by decreasing its polyubiquitination level. Specifically, 308th 347th lysine residues were critical for USP5-mediated deubiquitination stability. There five domains protein subsequent studies revealed that cryptic ZnF domain C-box interacted UBA1/UBA2 partly increased Notably, MafA MafB also members of family, however, failed deubiquitinate MafA, suggesting substrate specificity. functional studies, promoted transcriptional activity c-Maf. Consistent high level MM cells, highly expressed. When knocked down, underwent degradation. Interestingly, silence led apoptosis cells expressing not lacking indicating is cell proliferation survival. this finding, WP1130, an inhibitor several Dubs including USP5, suppressed induced apoptosis. overexpressed, WP1130-induced abolished. Taken together, these findings suggest regulates stability Targeting USP5/c-Maf axis could be potential strategy treatment.