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Functional characterization of NEDD8
in HDAC6 and ubiquitin mediated signaling pathway
Mira Kwon
Department of Biomedical sciences
The Graduate School, Ajou university
(Supervised by Professor Ho-chul Kang)
NEDD8 (Neural Precursor Cell Expressed, Developmentally Down-Regulated 8) is a small protein composed of 81 amino acids that has been known to play vital roles for versatile cellular processes including transcriptional regulation and DNA damage response (DDR). It is the most ubiquitin-like protein of 12 ULMs(ubiquitin like modifiers) with 60%
identity and 80% similarity with the amino acid sequences of ubiquitin and also has di-glycine motif in its c-terminus as ubiquitin. However, 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 human protein microarray system and identified Specific
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NEDD8 Interacting Proteins (SNIPs) including histone deacetylase 6 (HDAC6) and BAG3 involving in the selective autophagy. Intriguingly, HDAC6, the member of class II HDAC, is well known as one of acceptor of unanchored ubiquitin chains and regulates aggresome formation triggering autophagic degradation of ubiquitinated aggregates. However, it has not been elucidated whether it binds to NEDD8 or not. To dissect the interaction mechanism between HDAC6 and NEDD8, we generated several deletions and point mutations of HDAC6 or NEDD8 and found that NEDD8 binds to the BUZ /Znf-UBP domain on the C-terminus of HDAC6 via its di-glycine motif as ubiquitin. Intriguingly, we also identified that HDAC6 prefers to bind unanchored K11 ubiquitin rather than unanchored K63 chains, which has been known to strong binding target of HDAC6 in the process of aggresome formation. Next, we proceeded to analyze how the NEDD8, K11 unanchored ubiquitin chains and HDAC6 proteins interact with each other.
Remarkably, we observed that NEDD8 inhibited interaction between HDAC6 and unanchored K11 ubiquitin chains via its BUZ/zf-UBP domain.
This result suggested that the binding site for HDAC6 by NEDD8 or unanchored K11 ubiquitin chains is the same, indicating that the binding between these proteins can be controlled by the binding affinity of each protein or their protein levels in certain conditions of cells. The more important implication of these results is that NEDD8 may act as an