A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases

Fujita, Kyota; Nakamura, Yoko; Oka, Tsutomu; Ito, Hikaru; Tamura, Tomohide; Tagawa, Kazuhiko; Sasabe, Toshikazu; Katsuta, Asuka; Motoki, Kazumi; Shiwaku, Hiroki; Sone, Masaki; Yoshida, Chisato; Katsuno, Masahisa; Eishi, Yoshinobu; Murata, Miho; Taylor, J. Paul; Wanker, Erich E.; Kono, Kazuteru; Tashiro, Satoshi; Sobue, Gen; Spada, Albert R. La; Okazawa, Hitoshi

doi:10.1038/ncomms2828

Cited by 65 publications

(67 citation statements)

References 57 publications

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“…Besides, the nuclear activities of VCP are crucial in the protection against the neurotoxicity in polyglutamine diseases, or in the degradation of misfolded nuclear proteins during ERAD (46,47). Mutations in the N-domain also lead to reduced nuclear entry of VCP, although with unclear mechanism (35).…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

Wang

Qin

et al. 2016

Journal of Biological Chemistry

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Valosin-containing protein/p97(VCP) is a hexameric ATPase vital to protein degradation during endoplasmic reticulum stress. It regulates diverse cellular functions including autophagy, chromatin remodeling, and DNA repair. In addition, mutations in VCP cause inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD), as well as amyotrophic lateral sclerosis. Nevertheless, how the VCP activities were regulated and how the pathogenic mutations affect the function of VCP during stress are not unclear. Here we show that the small ubiquitin-like modifier (SUMO)-ylation of VCP is a normal stress response inhibited by the disease-causing mutations in the N-domain. Under oxidative and endoplasmic reticulum stress conditions, the SUMOylation of VCP facilitates the distribution of VCP to stress granules and nucleus, and promotes the VCP hexamer assembly. In contrast, pathogenic mutations in the VCP N-domain lead to reduced SUMOylation and weakened VCP hexamer formation upon stress. Defective SUMOylation of VCP also causes altered co-factor binding and attenuated endoplasmic reticulum-associated protein degradation. Furthermore, SUMO-defective VCP fails to protect against stress-induced toxicity in Drosophila. Therefore, our results have revealed SUMOylation as a molecular signaling switch to regulate the distribution and functions of VCP during stress response, and suggest that deficiency in VCP SUMOylation caused by pathogenic mutations will render cells vulnerable to stress insults.Valosin-containing protein (VCP/p97, cdc48, 2 is a highly conserved member of AAA (ATPase associated with diverse cellular activities) family proteins. It is mainly composed of N-domain and two ATPase domains. By forming a homohexamer and binding various co-factors via the N-domain, VCP helps to remodel, unfold, or degrade protein substrates using the energy derived from ATP hydrolysis (1-3). Due to its cellular abundance and broad interaction with a number of co-factors, key substrates, and regulators of the ubiquitin proteasome system, VCP has emerged as a vital modulator of a large variety of cellular activities, including protein degradation, ER stress response, autophagy/mitophagy, endosomal trafficking, cell cycle, and DNA repair (2, 5, 6). However, the factors that regulate VCP activities are not clear.The importance of VCP is also demonstrated by its association with cancer and degenerative diseases. VCP is highly expressed in non-small cell lung carcinoma (7), and its expression is correlated with tumor progression and prognosis (8). On the other hand, mutations in VCP have been associated with degenerative diseases, including inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS) (6, 9). Most pathogenic mutations of VCP are found in the N-domain, with a few in the ATPase domains (10). The pathology of VCP-associated degenerative diseases features ubiquitin-positive inclusions. Although some of the pathogenic VCP mutation...

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Section: Discussionmentioning

confidence: 99%

Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

Wang

Qin

et al. 2016

Journal of Biological Chemistry

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“…The perturbed effect could be partially rescued by ubiquitin overexpression. These observations can explain the observed damage found in DNA of cells with Huntingtin aggregates [35, 36]. Ubiquitin is present in most types of disease related cellular protein aggregates.…”

Section: Introductionmentioning

confidence: 90%

Ubiquitin Accumulation on Disease Associated Protein Aggregates Is Correlated with Nuclear Ubiquitin Depletion, Histone De-Ubiquitination and Impaired DNA Damage Response

et al. 2017

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Deposition of ubiquitin conjugates on inclusion bodies composed of protein aggregates is a definitive cytopathological hallmark of neurodegenerative diseases. We show that accumulation of ubiquitin on polyQ IB, associated with Huntington’s disease, is correlated with extensive depletion of nuclear ubiquitin and histone de-ubiquitination. Histone ubiquitination plays major roles in chromatin regulation and DNA repair. Accordingly, we observe that cells expressing IB fail to respond to radiomimetic DNA damage, to induce gamma-H2AX phosphorylation and to recruit 53BP1 to damaged foci. Interestingly ubiquitin depletion, histone de-ubiquitination and impaired DNA damage response are not restricted to PolyQ aggregates and are associated with artificial aggregating luciferase mutants. The longevity of brain neurons depends on their capacity to respond to and repair extensive ongoing DNA damage. Impaired DNA damage response, even modest one, could thus lead to premature neuron aging and mortality.

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“…However, ubiquitin-dependent functions of VCP are not limited to proteasomal degradation (Dantuma and Hoppe, 2012; Meyer et al, 2012) and include ubiquitin-selective autophagy (Ju et al, 2009; Tresse et al, 2010), the clearance of stress granules (Buchan et al, 2013), mitochondrial integrity (Bartolome et al, 2013), Parkin-dependent mitophagy (Kim et al, 2013), and the DNA damage response (Acs et al, 2011; Meerang et al, 2011). Overexpression of VCP mutants linked to MSP and ALS did not inhibit the UPS (Tresse et al, 2010), whereas some of the VCP-mediated events mentioned above were altered (Ju et al, 2009; Tresse et al, 2010; Bartolome et al, 2013; Fujita et al, 2013; Kim et al, 2013), suggesting that the pathology caused by mutant VCP likely involves essential ubiquitin-dependent processes that are different from proteasomal degradation.…”

Section: The Ubiquitin-proteasome System As Prime Suspectmentioning

confidence: 99%

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

Dantuma

Bott

2014

Front. Mol. Neurosci.

259

208

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The ubiquitin-proteasome system (UPS) has been implicated in neurodegenerative diseases based on the presence of deposits consisting of ubiquitylated proteins in affected neurons. It has been postulated that aggregation-prone proteins associated with these disorders, such as α-synuclein, β-amyloid peptide, and polyglutamine proteins, compromise UPS function, and delay the degradation of other proteasome substrates. Many of these substrates play important regulatory roles in signaling, cell cycle progression, or apoptosis, and their inadvertent stabilization due to an overloaded and improperly functioning UPS may thus be responsible for cellular demise in neurodegeneration. Over the past decade, numerous studies have addressed the UPS dysfunction hypothesis using various model systems and techniques that differ in their readout and sensitivity. While an inhibitory effect of some disease proteins on the UPS has been demonstrated, increasing evidence attests that the UPS remains operative in many disease models, which opens new possibilities for treatment. In this review, we will discuss the paradigm shift that repositioned the UPS from being a prime suspect in the pathophysiology of neurodegeneration to an attractive therapeutic target that can be harnessed to accelerate the clearance of disease-linked proteins.

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A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases

Cited by 65 publications

References 57 publications

Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

Ubiquitin Accumulation on Disease Associated Protein Aggregates Is Correlated with Nuclear Ubiquitin Depletion, Histone De-Ubiquitination and Impaired DNA Damage Response

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

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