Regulation of NUB1 Activity through Non-Proteolytic Mdm2-Mediated Ubiquitination

• Published in: PloS one Vol. 12; no. 1; p. e0169988
• Main Authors: Bonacci, Thomas, Audebert, Stéphane, Camoin, Luc, Baudelet, Emilie, Iovanna, Juan-Lucio, Soubeyran, Philippe
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.01.2017; Public Library of Science (PLoS)
• Subjects: Antifungal agents; Arginine; Biochemistry, Molecular Biology; Biology and Life Sciences; Cell cycle; Conjugation; Degradation; Enzymes; Genomics; HEK293 Cells; Humans; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Life Sciences; Lysine; Lysine - metabolism; MDM2 protein; Molecular modelling; Mutagenesis; Mutation; NEDD8 Protein; Physical Sciences; Plasmids; Proteasomes; Proteins; Proteolysis; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Regulation; Research and Analysis Methods; Transcription Factors - genetics; Transcription Factors - metabolism; Ubiquitin; Ubiquitin-proteasome system; Ubiquitin-protein ligase; Ubiquitination; Ubiquitins - genetics; Ubiquitins - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0169988

NUB1 (Nedd8 ultimate buster 1) is an adaptor protein which negatively regulates the ubiquitin-like protein Nedd8 as well as neddylated proteins levels through proteasomal degradation. However, molecular mechanisms underlying this function are not completely understood. Here, we report that the oncogenic E3 ubiquitin ligase Mdm2 is a new NUB1 interacting protein which induces its ubiquitination. Interestingly, we found that Mdm2-mediated ubiquitination of NUB1 is not a proteolytic signal. Instead of promoting the conjugation of polyubiquitin chains and the subsequent proteasomal degradation of NUB1, Mdm2 rather induces its di-ubiquitination on lysine 159. Importantly, mutation of lysine 159 into arginine inhibits NUB1 activity by impairing its negative regulation of Nedd8 and of neddylated proteins. We conclude that Mdm2 acts as a positive regulator of NUB1 function, by modulating NUB1 ubiquitination on lysine 159.