Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0073235
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dc.titleProteasome inhibition promotes Parkin-Ubc13 interaction and lysine 63-linked ubiquitination.
dc.contributor.authorLim G.G.
dc.contributor.authorNeurodegeneration Research Laboratory National Neuroscience Institute
dc.contributor.authorChew K.C.
dc.contributor.authorNg X.H.
dc.contributor.authorHenry-Basil A.
dc.contributor.authorSim R.W.
dc.contributor.authorTan J.M.
dc.contributor.authorChai C.
dc.date.accessioned2019-11-04T06:31:47Z
dc.date.available2019-11-04T06:31:47Z
dc.date.issued2013
dc.identifier.citationLim 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
dc.identifier.issn19326203
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/161353
dc.description.abstractDisruption 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.
dc.sourceUnpaywall
dc.subjectcarrier protein
dc.subjectlysine
dc.subjectnerve protein
dc.subjectparkin
dc.subjectproteasome
dc.subjectproteasome inhibitor
dc.subjectprotein binding
dc.subjectSNCAIP protein, human
dc.subjectUBE2N protein, human
dc.subjectubiquitin conjugating enzyme
dc.subjectubiquitin protein ligase
dc.subjectautophagy
dc.subjectdrug effects
dc.subjectgenetics
dc.subjectHEK293 cell line
dc.subjecthomeostasis
dc.subjecthuman
dc.subjectmetabolism
dc.subjectmutation
dc.subjectprotein degradation
dc.subjectprotein transport
dc.subjectubiquitination
dc.subjectAutophagy
dc.subjectCarrier Proteins
dc.subjectHEK293 Cells
dc.subjectHomeostasis
dc.subjectHumans
dc.subjectLysine
dc.subjectMutation
dc.subjectNerve Tissue Proteins
dc.subjectProteasome Endopeptidase Complex
dc.subjectProteasome Inhibitors
dc.subjectProtein Binding
dc.subjectProtein Transport
dc.subjectProteolysis
dc.subjectUbiquitin-Conjugating Enzymes
dc.subjectUbiquitin-Protein Ligases
dc.subjectUbiquitination
dc.typeArticle
dc.contributor.departmentDEPT OF PHYSIOLOGY
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.contributor.departmentINSTITUTE OF MOLECULAR & CELL BIOLOGY
dc.contributor.departmentDEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL)
dc.description.doi10.1371/journal.pone.0073235
dc.description.sourcetitlePloS one
dc.description.volume8
dc.description.issue9
dc.description.pagee73235
dc.published.statePublished
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