Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0073235
Title: Proteasome inhibition promotes Parkin-Ubc13 interaction and lysine 63-linked ubiquitination.
Authors: Lim G.G. 
Neurodegeneration Research Laboratory National Neuroscience Institute
Chew K.C. 
Ng X.H.
Henry-Basil A.
Sim R.W.
Tan J.M. 
Chai C.
Keywords: carrier protein
lysine
nerve protein
parkin
proteasome
proteasome inhibitor
protein binding
SNCAIP protein, human
UBE2N protein, human
ubiquitin conjugating enzyme
ubiquitin protein ligase
autophagy
drug effects
genetics
HEK293 cell line
homeostasis
human
metabolism
mutation
protein degradation
protein transport
ubiquitination
Autophagy
Carrier Proteins
HEK293 Cells
Homeostasis
Humans
Lysine
Mutation
Nerve Tissue Proteins
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Protein Binding
Protein Transport
Proteolysis
Ubiquitin-Conjugating Enzymes
Ubiquitin-Protein Ligases
Ubiquitination
Issue Date: 2013
Citation: Lim G.G., Neurodegeneration Research Laboratory National Neuroscience Institute, Chew K.C., Ng X.H., Henry-Basil A., Sim R.W., Tan J.M., Chai C. (2013). Proteasome inhibition promotes Parkin-Ubc13 interaction and lysine 63-linked ubiquitination.. PloS one 8 (9) : e73235. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0073235
Abstract: Disruption of the ubiquitin-proteasome system, which normally identifies and degrades unwanted intracellular proteins, is thought to underlie neurodegeneration. Supporting this, mutations of Parkin, a ubiquitin ligase, are associated with autosomal recessive parkinsonism. Remarkably, Parkin can protect neurons against a wide spectrum of stress, including those that promote proteasome dysfunction. Although the mechanism underlying the preservation of proteasome function by Parkin is hitherto unclear, we have previously proposed that Parkin-mediated K63-linked ubiquitination (which is usually uncoupled from the proteasome) may serve to mitigate proteasomal stress by diverting the substrate load away from the machinery. By means of linkage-specific antibodies, we demonstrated here that proteasome inhibition indeed promotes K63-linked ubiquitination of proteins especially in Parkin-expressing cells. Importantly, we further demonstrated that the recruitment of Ubc13 (an E2 that mediates K63-linked polyubiquitin chain formation exclusively) by Parkin is selectively enhanced under conditions of proteasomal stress, thus identifying a mechanism by which Parkin could promote K63-linked ubiquitin modification in cells undergoing proteolytic stress. This mode of ubiquitination appears to facilitate the subsequent clearance of Parkin substrates via autophagy. Consistent with the proposed protective role of K63-linked ubiquitination in times of proteolytic stress, we found that Ubc13-deficient cells are significantly more susceptible to cell death induced by proteasome inhibitors compared to their wild type counterparts. Taken together, our study suggests a role for Parkin-mediated K63 ubiquitination in maintaining cellular protein homeostasis, especially during periods when the proteasome is burdened or impaired.
Source Title: PloS one
URI: https://scholarbank.nus.edu.sg/handle/10635/161353
ISSN: 19326203
DOI: 10.1371/journal.pone.0073235
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