NEDD8 (Neural Precursor Cell Expressed, Developmentally Down-Regulated 8) has been known that it plays important roles for versatile cellular processes including transcription and DNA damage response (DDR) as one of ubiquitin like modifiers (ULMs). Among 12 ULMs, NEDD8 has the most similar structure with ubiquitin. Although NEDD8 has highly conserved sequence homology to ubiquitin (58% identity and 80% similarity), it still remains unclear what is the distinct role of NEDD8 compare to function of ubiquitin in cells. To address this point, we screened NEDD8 binding proteins using a protein microarray system, and identify Specific NEDD8 Interacting Proteins (SNIPs) such as histone deacetylase 6 (HDAC6) and BAG3 involving in the selective autophagy. Intriguingly, HDAC6 is known as one of ubiquitin chain acceptor but it has not been elucidated whether it binds to ubiquitin monomer or not. To dissect interplay mechanism between HDAC6 and EDD8, we generated deletion mutant of HDAC6 and found that NEDD8 strongly interacts with Zinc-finger type ubiquitin binding domain on c-termini of HDAC6 as well as ubiquitin chains. These data suggested that NEDD8 seems to be a competitor of ubiquitin chains for HDAC6 activity. Besides, NEDD8 interacts with HDAC6 via its di-glycine motif as well as ubiquitin. Taken together, our data suggested that NEDD8 may act as a negative regulator or competitor for the ubiquitin/HDAC6 coupled diverse cellular processes.
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