Regulation of parkin and PINK1 by neddylation

Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Human Molecular Genetics (Impact Factor: 6.39). 03/2012; 21(11):2514-23. DOI: 10.1093/hmg/dds070
Source: PubMed


Neddylation is a posttranslational modification that plays important roles in regulating protein structure and function by covalently conjugating NEDD8, an ubiquitin-like small molecule, to the substrate. Here, we report that Parkinson's disease (PD)-related parkin and PINK1 are NEDD8 conjugated. Neddylation of parkin and PINK1 results in increased E3 ligase activity of parkin and selective stabilization of the 55 kDa PINK1 fragment. Expression of dAPP-BP1, a NEDD8 activation enzyme subunit, in Drosophila suppresses abnormalities induced by dPINK1 RNAi. PD neurotoxin MPP(+) inhibits neddylation of both parkin and PINK1. NEDD8 immunoreactivity is associated with Lewy bodies in midbrain dopaminergic neurons of PD patients. Together, these results suggest that parkin and PINK1 are regulated by neddylation and that impaired NEDD8 modification of these proteins likely contributes to PD pathogenesis.

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Available from: W. Andy Tao, Jan 22, 2014
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    • "Neddylation of PINK1 leads to stabilization of a PINK1 fragment with unknown functional significance [33]. Moreover, expression of NAE1 partially rescues abnormalities induced by PINK1 knockdown in Drosophila , while neurotoxin MPP(+) suppresses the neddylation of parkin and PINK1 in HEK293 cells [33] [34], suggesting that neddylation of parkin could be protective against stress. Further studies to determine the consequence of neddylation of parkin and PINK1 on mitochondria turnover are clearly warranted. "
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    ABSTRACT: Neddylation is a post-translational protein modification that conjugates a ubiquitin-like protein NEDD8 to target proteins. Similar to ubiquitination, neddylation is mediated by a cascade of three NEDD8 specific enzymes, an E1 activating enzyme, an E2 conjugating enzyme and one of the several E3 ligases. Neddylation is countered by the action of deneddylases via a process termed deneddylation. By altering the substrate's conformation, stability, subcellular localization or binding affinity to DNA or proteins, neddylation regulates diverse cellular processes including the ubiquitin-proteasome system-mediated protein degradation, protein transcription, cell signaling etc. Dysregulation of neddylation has been linked to cancer, neurodegenerative disorders, and more recently, cardiac disease. Here we comprehensively overview the biochemistry, the proteome and the biological function of neddylation. We also summarize the recent progress in revealing the physiological and pathological role of neddylation and deneddylation in the heart.
    Full-text · Article · Jan 2014 · American Journal of Cardiovascular Disease
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    ABSTRACT: Parkin is an E3 ubiquitin ligase mutated in autosomal recessive juvenile Parkinson's disease. In addition, it is a putative tumour suppressor, and has roles outside its enzymatic activity. It is critical for mitochondrial clearance through mitophagy, and is an essential protein in most eukaryotes. As such, it is a tightly controlled protein, regulated through an array of external interactions with multiple proteins, posttranslational modifications including phosphorylation and S-nitrosylation, and self-regulation through internal associations. In this review, we highlight some of the recent studies into Parkin regulation and discuss future challenges for gaining a full molecular understanding of the regulation of Parkin E3 ligase activity.
    No preview · Article · Apr 2012 · Cellular and Molecular Life Sciences CMLS
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    ABSTRACT: Of all ubiquitin-like proteins, Rub1 (Nedd8 in mammals) is the closest kin of ubiquitin. We show by NMR that structurally Rub1 and ubiquitin are fundamentally similar as well. Despite these profound similarities, the prevalence of Rub1/Nedd8 or ubiquitin as modifiers of the proteome is starkly different, and their attachment to specific substrates performs different functions. Recently, some proteins, including p53, p73, EGFR, caspase-7, and Parkin, have been shown to be modified by both Rub1/Nedd8 and ubiquitin within cells. To understand whether and how it may be possible to distinguish among the same target protein modified by Rub1 or ubiquitin or both, we examined if ubiquitin receptors can differentiate between Rub1 and ubiquitin. Surprisingly, Rub1 interacts with proteasome ubiquitin-shuttle proteins comparably to ubiquitin, but binds weaker to a proteasomal ubiquitin-receptor Rpn10. We identified Rub1-ubiquitin heteromers in yeast and Nedd8-Ub heteromers in human cells. We validate that in human cells and in vitro, human Rub1 (Nedd8) forms chains with ubiquitin where it acts as a chain terminator. Interestingly, enzymatically assembled K48-linked Rub1-ubiquitin heterodimers are recognized by various proteasomal ubiquitin-shuttles and receptors comparably to K48-linked ubiquitin-homodimers. Furthermore, these heterologous chains are cleaved by COP9 signalosome or 26S proteasome. A derubylation function of the proteasome expands the repertoire of its enzymatic activities. In contrast, Rub1 conjugates may be somewhat resilient to action of other canonical DUBs. Taken together, these findings suggest that once Rub1/Nedd8 is channeled into ubiquitin-pathways, it is recognized essentially like ubiquitin.
    Preview · Article · Oct 2012 · Molecular &amp Cellular Proteomics
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