Ataxin-3 Regulates Aggresome Formation of Copper-Zinc Superoxide Dismutase (SOD1) by Editing K63-linked Polyubiquitin Chains

Wang, Hongfeng; Ying, Zheng; Wang, Guanghui

doi:10.1074/jbc.m111.299990

Cited by 65 publications

(44 citation statements)

References 44 publications

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“…it is conceivable that polyubiquitin chains including K63-linked chains are progressively modified by deubiquitinating enzymes with time, which could present a confounding factor. Lending support to this, Wang and colleagues [43] recently demonstrated that the formation of aggresomes mediated by mutant superoxide dismutase 1 (SOD1) is dependent on ataxin 3-catalyzed editing of K63-linked polyubiquitin chain on SOD1 (presumably to a correct length). Conversely, knockdown of ataxin-3 decreases mutant SOD1 aggresome formation and increases cell death induced by mutant SOD1.…”

Section: Discussionmentioning

confidence: 99%

Proteasome Inhibition Promotes Parkin-Ubc13 Interaction and Lysine 63-Linked Ubiquitination

Lim

Chew

et al. 2013

PLoS ONE

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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.

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Section: Discussionmentioning

confidence: 99%

Proteasome Inhibition Promotes Parkin-Ubc13 Interaction and Lysine 63-Linked Ubiquitination

Lim

Chew

et al. 2013

PLoS ONE

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“…If the concentration of a certain protein species cannot be controlled by the proteasome, it is sequestered into aggregates, targeted for autophagy (45), and degraded in the lysosome (43). When it comes to the actual handling and molecular environment of the aggregates, this process seems, in turn, to operate at two gears depending on load: either nascent aggregates are cleared directly in the cytosol or if this first line of defense becomes overwhelmed, they are captured in aggresomes for degradation by other more specialized autophagy pathways (43,44). Although the whole-tissue kinetics in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The better option could be to target directly elongation and fragmentation. It is, thus, interesting that the foremost apparent in vivo response to protein aggregation involves sequestration, packing, and coating (38,43,44), all of which are expected to modulate the fibrils' growth dynamics.…”

Section: Discussionmentioning

confidence: 99%

SOD1 aggregation in ALS mice shows simplistic test tube behavior

Lang

Zetterström

Brännström

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

123

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A longstanding challenge in studies of neurodegenerative disease has been that the pathologic protein aggregates in live tissue are not amenable to structural and kinetic analysis by conventional methods. The situation is put in focus by the current progress in demarcating protein aggregation in vitro, exposing new mechanistic details that are now calling for quantitative in vivo comparison. In this study, we bridge this gap by presenting a direct comparison of the aggregation kinetics of the ALS-associated protein superoxide dismutase 1 (SOD1) in vitro and in transgenic mice. The results based on tissue sampling by quantitative antibody assays show that the SOD1 fibrillation kinetics in vitro mirror with remarkable accuracy the spinal cord aggregate buildup and disease progression in transgenic mice. This similarity between in vitro and in vivo data suggests that, despite the complexity of live tissue, SOD1 aggregation follows robust and simplistic rules, providing new mechanistic insights into the ALS pathology and organism-level manifestation of protein aggregation phenomena in general.superoxide dismutase 1 | aggregation | transgenic mice | aggregation kinetics

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“…On the other hand, JAMMs, a family of DUBs with zinc metalloprotease activity, share the specificity for Lys63‐linked polyubiquitin 34, 35. The Ub editing activity of Josephin ATXN3 is restricted specifically to K63‐linked Ub chains and mixed‐linkage Ub chains 36. Given the fact that DUBs regulate the turnover rate, activation, recycling and localization of multiple proteins, they are central players in governing the signalling pathways and cell homeostasis.…”

Section: Deubiquitylation Enzymesmentioning

confidence: 99%

The role of K63‐linked polyubiquitination in cardiac hypertrophy

Ponnusamy

Xin

et al. 2018

J Cellular Molecular Medi

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Ubiquitination, also known as ubiquitylation, is a vital post‐translational modification of proteins that play a crucial role in the multiple biological processes including cell growth, proliferation and apoptosis. K63‐linked ubiquitination is one of the vital post‐translational modifications of proteins that are involved in the activation of protein kinases and protein trafficking during cell survival and proliferation. It also contributes to the development of various disorders including cancer, neurodegeneration and cardiac hypertrophy. In this review, we summarize the role of K63‐linked ubiquitination signalling in protein kinase activation and its implications in cardiac hypertrophy. We have also provided our perspectives on therapeutically targeting K63‐linked ubiquitination in downstream effector molecules of growth factor receptors for the treatment of cardiac hypertrophy.

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Ataxin-3 Regulates Aggresome Formation of Copper-Zinc Superoxide Dismutase (SOD1) by Editing K63-linked Polyubiquitin Chains

Cited by 65 publications

References 44 publications

Proteasome Inhibition Promotes Parkin-Ubc13 Interaction and Lysine 63-Linked Ubiquitination

Proteasome Inhibition Promotes Parkin-Ubc13 Interaction and Lysine 63-Linked Ubiquitination

SOD1 aggregation in ALS mice shows simplistic test tube behavior

The role of K63‐linked polyubiquitination in cardiac hypertrophy

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