Ube2w and Ataxin-3 Coordinately Regulate the Ubiquitin Ligase CHIP

Scaglione, K. Matthew; Zavodszky, Eszter; Todi, Sokol V.; Patury, Srikanth; Xu, Ping; Rodríguez-Lebrón, Edgardo; Fischer, Svetlana; Konen, John R.; Djarmati, Ana; Peng, Junmin; Gestwicki, Jason E.; Paulson, Henry L.

doi:10.1016/j.molcel.2011.05.036

Cited by 149 publications

(193 citation statements)

References 60 publications

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“…For example, DUBs can reverse auto-ubiquitylation of E3 ligases and prevent their degradation. Moreover, DUBs are also targets of E3 ligasemediated ubiquitylation (Huang et al, 2011;Mashtalir et al, 2014;Scaglione et al, 2011;Seki et al, 2013;Todi et al, 2009;Wijnhoven et al, 2015). Importantly, in recent years it has become clear that DUBs and E3 ligases can co-operate to dictate the outcome of protein ubiquitylation.…”

Section: Regulating Dub Function By Antagonizing Ubiquitylationmentioning

confidence: 99%

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Leznicki

Kulathu

2017

Journal of Cell Science

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Deubiquitylating (or deubiquitinating) enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this post-translational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns. Central among these is the conundrum of how the small number of ∼100 DUBs encoded in the human genome is capable of regulating the thousands of ubiquitin modification sites detected in human cells. This Commentary addresses the biological mechanisms employed to modulate and expand the functions of DUBs, and sets directions for future research aimed at elucidating the details of these fascinating processes.This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: 'Exploitation of the host cell ubiquitin machinery by microbial effector proteins' by Yi-Han Lin and Matthias P. Machner (J. Cell Sci. 130, 1985-1996. 'Cell scientist to watch -Mads Gyrd-Hansen' (J. Cell Sci. 130, 1981-1983.

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Section: Regulating Dub Function By Antagonizing Ubiquitylationmentioning

confidence: 99%

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Leznicki

Kulathu

2017

Journal of Cell Science

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“…Two reported UBE2W substrates are the neurodegenerative disease proteins Ataxin-3 and Tau (17,18), suggesting a potentially important role for UBE2W in brain. To eliminate UBE2W expression selectively in the central nervous system (CNS), we crossed Ube2w Flox/Flox mice with Nestin promoter-driven, Cre recombinase-expressing mice.…”

Section: Isoform 1 Is the Major Expressed Ube2w Isoform In Mouse-mentioning

confidence: 99%

Loss of the Ubiquitin-conjugating Enzyme UBE2W Results in Susceptibility to Early Postnatal Lethality and Defects in Skin, Immune, and Male Reproductive Systems

Wang¹,

Merillat²,

Vincent

et al. 2016

Journal of Biological Chemistry

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UBE2W ubiquitinates N termini of proteins rather than internal lysine residues, showing a preference for substrates with intrinsically disordered N termini. The in vivo functions of this intriguing E2, however, remain unknown. We generated Ube2w germ line KO mice that proved to be susceptible to early postnatal lethality without obvious developmental abnormalities. Although the basis of early death is uncertain, several organ systems manifest changes in Ube2w KO mice. Newborn Ube2w KO mice often show altered epidermal maturation with reduced expression of differentiation markers. Mirroring higher UBE2W expression levels in testis and thymus, Ube2w KO mice showed a disproportionate decrease in weight of these two organs (ϳ50%), suggesting a functional role for UBE2W in the immune and male reproductive systems. Indeed, Ube2w KO mice displayed sustained neutrophilia accompanied by increased G-CSF signaling and testicular vacuolation associated with decreased fertility. Proteomic analysis of a vulnerable organ, presymptomatic testis, showed a preferential accumulation of disordered proteins in the absence of UBE2W, consistent with the view that UBE2W preferentially targets disordered polypeptides. These mice further allowed us to establish that UBE2W is ubiquitously expressed as a single isoform localized to the cytoplasm and that the absence of UBE2W does not alter cell viability in response to various stressors. Our results establish that UBE2W is an important, albeit not essential, protein for early postnatal survival and normal functioning of multiple organ systems.

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“…The expansion of the polyQ tract in ataxin-3 may alter the dynamics of ataxin-3 and CHIP interaction, targeting CHIP for degradation. In fact, expanded ataxin-3 presents an increased affinity for CHIP, and decreased levels of CHIP were found in a SCA3 mouse model [182]. Consistently with its function in transcription, expression of mutant ataxin-3 in SCA3 transgenic mice altered the expression of several genes including those involved in the heat shock response [31].…”

Section: Spinocerebellar Ataxias and Dentatorubral-pallidoluysian Atrmentioning

confidence: 99%

“…Ataxin-3 has ubiquitin-protease activity and up to three ubiquitin-binding motifs, being thought to directly regulate ubiquitination-dependent degradation pathways [181]. Additionally, ataxin-3 was shown to interact with the co-chaperone and E3 ligase CHIP and suggested to promote the turnover of CHIP substrates [182]. The expansion of the polyQ tract in ataxin-3 may alter the dynamics of ataxin-3 and CHIP interaction, targeting CHIP for degradation.…”

Section: Spinocerebellar Ataxias and Dentatorubral-pallidoluysian Atrmentioning

confidence: 99%

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

2016

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Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs, and suggests different interactions with the cellular proteostasis machinery. Molecular chaperones are key elements of the proteostasis machinery and therapeutic targets for neurodegeneration. Here we provide a focused review on Hsp90, Hsp70, and their cochaperones, and how their genetic or pharmacological modulation affects the proteostasis and disease phenotypes in cellular and animal models of polyglutamine disorders. The emerging picture is that, in principle, Hsp70 modulation may be more amenable for long-term treatment by promoting a more selective clearance of mutant proteins than Hsp90 modulation, which may further decrease the necessary wild-type counterparts. It seems, nevertheless, unlikely that a single Hsp70 modulator will benefit all polyglutamine diseases. Indeed, available data, together with insights from effects on tau and alpha-synuclein in models of Alzheimer's and Parkinson's diseases, indicates that Hsp70 modulators may lead to different effects on the proteostasis of different mutant and wild-type client proteins. Future studies should include the further development of isoform selective inhibitors, namely to avoid off-target effects on Hsp in the mitochondria, and their characterization in distinct polyglutamine disease models to account for client protein-specific differences.

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Ube2w and Ataxin-3 Coordinately Regulate the Ubiquitin Ligase CHIP

Cited by 149 publications

References 60 publications

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Loss of the Ubiquitin-conjugating Enzyme UBE2W Results in Susceptibility to Early Postnatal Lethality and Defects in Skin, Immune, and Male Reproductive Systems

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

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