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Virginia Kimonis - One of the best experts on this subject based on the ideXlab platform.
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genotype phenotype study in patients with Valosin Containing Protein mutations associated with multisystem Proteinopathy
Clinical Genetics, 2018Co-Authors: Ebaa Alobeidi, Tahseen Mozaffar, Sejad Altahan, Molly Omizo, Charles D. Smith, Abhilasha Surampalli, Namita Goyal, Annabel K Wang, Andreas Hermann, Virginia KimonisAbstract:Mutations in Valosin-Containing Protein (VCP), an ATPase involved in Protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem Proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males, 113 females) from 36 families carrying 15 different VCP mutations. We analyzed correlation between the different mutations and prevalence, age of onset and severity of myopathy, PDB, and FTD, and other comorbidities. Myopathy, PDB and FTD was present in 90%, 42% and 30% of the patients respectively, beginning at an average age of 43 years, 41 years, and 56 years respectively. Approximately 9% of patients with VCP mutations had an ALS phenotype, 4% had been diagnosed with Parkinson's disease (PD), and 2% had been diagnosed with Alzheimer's disease (AD). Large inter and intra-familial variation made establishing correlations difficult. We did not find a correlation between the mutation type and the incidence of any of the clinical features associated with VCP disease, except for the absence of PDB with the R159C mutation in our cohort and R159C having a later age of onset of myopathy compared to other molecular subtypes.
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Genotype‐phenotype study in patients with Valosin‐Containing Protein mutations associated with multisystem Proteinopathy
Clinical Genetics, 2017Co-Authors: Ebaa Al-obeidi, Tahseen Mozaffar, Molly Omizo, Charles D. Smith, Abhilasha Surampalli, Namita Goyal, Annabel K Wang, Andreas Hermann, Sejad Al-tahan, Virginia KimonisAbstract:Mutations in Valosin-Containing Protein (VCP), an ATPase involved in Protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem Proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males, 113 females) from 36 families carrying 15 different VCP mutations. We analyzed correlation between the different mutations and prevalence, age of onset and severity of myopathy, PDB, and FTD, and other comorbidities. Myopathy, PDB and FTD was present in 90%, 42% and 30% of the patients respectively, beginning at an average age of 43 years, 41 years, and 56 years respectively. Approximately 9% of patients with VCP mutations had an ALS phenotype, 4% had been diagnosed with Parkinson's disease (PD), and 2% had been diagnosed with Alzheimer's disease (AD). Large inter and intra-familial variation made establishing correlations difficult. We did not find a correlation between the mutation type and the incidence of any of the clinical features associated with VCP disease, except for the absence of PDB with the R159C mutation in our cohort and R159C having a later age of onset of myopathy compared to other molecular subtypes.
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activation of the nlrp3 inflammasome is associated with Valosin Containing Protein myopathy
Inflammation, 2017Co-Authors: Angele Nalbandian, Virginia Kimonis, Katrina J Llewellyn, Arif A Khan, Ruchi Srivastava, Nora Shukr, Yasmin Fazli, Lbachir BenmohamedAbstract:Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-Containing Protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with Valosin-Containing Protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1β, and IL-18 in the quadriceps muscles of VCPR155H/+ heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β(+)F4/80(+)Ly6C(+) inflammatory macrophages that infiltrate the muscles of VCPR155H/+ mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β(+)F4/80(+)Ly6C(+) macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCPR155H/+ mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80(+)Ly6C(+)IL-1β(+) macrophage infiltrates in the muscle, and significantly ameliorated muscle strength. Together, these results suggest that (i) NLRP3 inflammasome and local IL-1β(+)F4/80(+)Ly6C(+) inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.
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targeted excision of vcp r155h mutation by cre loxp technology as a promising therapeutic strategy for Valosin Containing Protein disease
Human Gene Therapy Methods, 2015Co-Authors: Angele Nalbandian, Katrina J Llewellyn, Christopher Nguyen, Edward S Monuki, Virginia KimonisAbstract:Abstract Inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia is attributed to mutations in the Valosin-Containing Protein (VCP) gene, mapped to chromosomal region 9p13.3–12. Affected individuals exhibit scapular winging and die from progressive muscle weakness and cardiac and respiratory failure in their 40s to 50s. Mutations in the VCP gene have also been associated with amyotrophic lateral sclerosis in 10–15% of individuals with hereditary inclusion body myopathy and 2–3% of isolated familial amyotrophic lateral sclerosis. Currently, there are no effective treatments for VCP-related myopathy or dementia. To determine the effects of targeted excision of the most common R155H mutation in VCP disease, we generated the Cre-ER™-VCPR155H/+ tamoxifen-inducible model. We administered tamoxifen (0.12 mg/g body weight) or corn oil (vehicle) to the pregnant dams by oral gavage and monitored survival and muscle strength measurements of the pups until 18 months of age. We ...
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Valosin-Containing Protein (VCP) Disease and Familial Alzheimer’s Disease: Contrasts and Overlaps
The Clinical Spectrum of Alzheimer's Disease -The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies, 2011Co-Authors: Charles D. Smith, Giles D J Watts, Angele Nalbandian, Mallikarjun Badadani, Jouni Vesa, Vincent J Caiozzo, Sandra Donkervoort, Barbara Martin, Virginia KimonisAbstract:Contrasts between two entities may be illuminating because of the emphasis on what each is not. Here we describe two Proteinopathies producing brain neurodegeneration in mature adults, autosomal dominant Valosin-Containing Protein (VCP) disease and Familial Alzheimer’s disease (FAD) caused by presenillin-1 (PSEN1) mutations, illustrating both contrasting patterns of clinical presentation and known neuropathologic and imaging features, and points of congruence. Mutations primarily in the ubiquitin binding domain of the VCP gene cause frontotemporal dementia as part of a rare but important disorder that also encompasses inclusion body myopathy, Paget disease of bone, and in some cases, motor neuron disease. The VCP dementia has onset in the 50s, characterized by abulia, expressive language loss, and executive dysfunction. The pattern of degeneration generally is anterior, in frontal and temporal lobes, involving neuronal nuclear inclusions of ubiquitin and TAR DNA binding Protein 43 (TDP-43), but not amyloid or tau. The most common mutations causing FAD occur in the PSEN1 gene. The associated dementia has onset in the late 40s, characterized by early memory loss and diffuse amyloid vasculopathy, and posteriorly distributed neuritic amyloid plaque and neurofibrillary tau pathology in medial temporal and parietal lobes, but not ubiquitin or TDP-43. Nonetheless, both VCP and PSEN1 pathologies have extensively documented abnormalities in similar Protein processing pathways.
Brett D Lindenbach - One of the best experts on this subject based on the ideXlab platform.
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a sensitive yellow fever virus entry reporter identifies Valosin Containing Protein vcp p97 as an essential host factor for flavivirus uncoating
Mbio, 2020Co-Authors: Harish N. Ramanathan, Florian Douam, Jinhong Chang, Priscilla L Yang, John W. Schoggins, Alexander Ploss, Shuo Zhang, Brett D LindenbachAbstract:ABSTRACT While the basic mechanisms of flavivirus entry and fusion are understood, little is known about the postfusion events that precede RNA replication, such as nucleocapsid disassembly. We describe here a sensitive, conditionally replication-defective yellow fever virus (YFV) entry reporter, YFVΔSK/Nluc, to quantitively monitor the translation of incoming, virus particle-delivered genomes. We validated that YFVΔSK/Nluc gene expression can be neutralized by YFV-specific antisera and requires known flavivirus entry pathways and cellular factors, including clathrin- and dynamin-mediated endocytosis, endosomal acidification, YFV E glycoProtein-mediated fusion, and cellular LY6E and RPLP1 expression. The initial round of YFV translation was shown to require cellular ubiquitylation, consistent with recent findings that dengue virus capsid Protein must be ubiquitylated in order for nucleocapsid uncoating to occur. Importantly, translation of incoming YFV genomes also required Valosin-Containing Protein (VCP)/p97, a cellular ATPase that unfolds and extracts ubiquitylated client Proteins from large complexes. RNA transfection and washout experiments showed that VCP/p97 functions at a postfusion, pretranslation step in YFV entry. Finally, VCP/p97 activity was required by other flaviviruses in mammalian cells and by YFV in mosquito cells. Together, these data support a critical role for VCP/p97 in the disassembly of incoming flavivirus nucleocapsids during a postfusion step in virus entry. IMPORTANCE Flaviviruses are an important group of RNA viruses that cause significant human disease. The mechanisms by which flavivirus nucleocapsids are disassembled during virus entry remain unclear. Here, we used a yellow fever virus entry reporter, which expresses a sensitive reporter enzyme but does not replicate, to show that nucleocapsid disassembly requires the cellular Protein-disaggregating enzyme Valosin-Containing Protein, also known as p97.
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A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating.
Mbio, 2020Co-Authors: Harish N. Ramanathan, Florian Douam, Jinhong Chang, Priscilla L Yang, John W. Schoggins, Alexander Ploss, Shuo Zhang, Brett D LindenbachAbstract:ABSTRACT While the basic mechanisms of flavivirus entry and fusion are understood, little is known about the postfusion events that precede RNA replication, such as nucleocapsid disassembly. We describe here a sensitive, conditionally replication-defective yellow fever virus (YFV) entry reporter, YFVΔSK/Nluc, to quantitively monitor the translation of incoming, virus particle-delivered genomes. We validated that YFVΔSK/Nluc gene expression can be neutralized by YFV-specific antisera and requires known flavivirus entry pathways and cellular factors, including clathrin- and dynamin-mediated endocytosis, endosomal acidification, YFV E glycoProtein-mediated fusion, and cellular LY6E and RPLP1 expression. The initial round of YFV translation was shown to require cellular ubiquitylation, consistent with recent findings that dengue virus capsid Protein must be ubiquitylated in order for nucleocapsid uncoating to occur. Importantly, translation of incoming YFV genomes also required Valosin-Containing Protein (VCP)/p97, a cellular ATPase that unfolds and extracts ubiquitylated client Proteins from large complexes. RNA transfection and washout experiments showed that VCP/p97 functions at a postfusion, pretranslation step in YFV entry. Finally, VCP/p97 activity was required by other flaviviruses in mammalian cells and by YFV in mosquito cells. Together, these data support a critical role for VCP/p97 in the disassembly of incoming flavivirus nucleocapsids during a postfusion step in virus entry. IMPORTANCE Flaviviruses are an important group of RNA viruses that cause significant human disease. The mechanisms by which flavivirus nucleocapsids are disassembled during virus entry remain unclear. Here, we used a yellow fever virus entry reporter, which expresses a sensitive reporter enzyme but does not replicate, to show that nucleocapsid disassembly requires the cellular Protein-disaggregating enzyme Valosin-Containing Protein, also known as p97.
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a sensitive yellow fever virus entry reporter identifies Valosin Containing Protein vcp p97 as an essential host factor for flavivirus uncoating
bioRxiv, 2019Co-Authors: Harish N. Ramanathan, Florian Douam, Jinhong Chang, Priscilla L Yang, Alexander Ploss, Shuo Zhang, Brett D LindenbachAbstract:While the basic mechanisms of flavivirus entry and fusion are understood, little is known about the post-fusion events that precede RNA replication, such as nucleocapsid disassembly. We describe here a sensitive, conditionally replication-defective yellow fever virus (YFV) entry reporter, YFV{Delta}SK/Nluc, to quantitively monitor the translation of incoming, virus particle-delivered genomes. We validated that YFV{Delta}SK/Nluc gene expression can be neutralized by YFV-specific antisera and requires known flavivirus entry pathways, including clathrin- and dynamin-mediated endocytosis, endosomal acidification, YFV E glycoProtein-mediated fusion, and cellular LY6E expression; however, as expected, gene expression from the defective reporter virus was insensitive to a small molecule inhibitor of YFV RNA replication. YFV{Delta}SK/Nluc gene expression was also shown to require cellular ubiquitylation, consistent with recent findings that dengue virus capsid Protein must be ubiquitylated in order for nucleocapsid uncoating to occur, as well as Valosin-Containing Protein (VCP)/p97, a cellular ATPase that unfolds and extracts ubiquitylated client Proteins from large macromolecular complexes. RNA transfection and washout experiments showed that VCP/p97 functions at a post-fusion, pre-translation step in YFV entry. Together, these data support a critical role for VCP/p97 in the disassembly of incoming flavivirus nucleocapsids during a post-fusion step in virus entry.nnIMPORTANCEFlaviviruses are an important group of RNA viruses that cause significant human disease. The mechanisms by which flavivirus nucleocapsids are disassembled during virus entry remain unclear. Here we show that the yellow fever virus nucleocapsid disassembly requires the cellular Protein-disaggregating enzyme Valosin-Containing Protein, also known as p97.
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A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating
bioRxiv, 2019Co-Authors: Harish N. Ramanathan, Florian Douam, Jinhong Chang, Priscilla L Yang, Alexander Ploss, Shuo Zhang, Brett D LindenbachAbstract:While the basic mechanisms of flavivirus entry and fusion are understood, little is known about the post-fusion events that precede RNA replication, such as nucleocapsid disassembly. We describe here a sensitive, conditionally replication-defective yellow fever virus (YFV) entry reporter, YFV{Delta}SK/Nluc, to quantitively monitor the translation of incoming, virus particle-delivered genomes. We validated that YFV{Delta}SK/Nluc gene expression can be neutralized by YFV-specific antisera and requires known flavivirus entry pathways, including clathrin- and dynamin-mediated endocytosis, endosomal acidification, YFV E glycoProtein-mediated fusion, and cellular LY6E expression; however, as expected, gene expression from the defective reporter virus was insensitive to a small molecule inhibitor of YFV RNA replication. YFV{Delta}SK/Nluc gene expression was also shown to require cellular ubiquitylation, consistent with recent findings that dengue virus capsid Protein must be ubiquitylated in order for nucleocapsid uncoating to occur, as well as Valosin-Containing Protein (VCP)/p97, a cellular ATPase that unfolds and extracts ubiquitylated client Proteins from large macromolecular complexes. RNA transfection and washout experiments showed that VCP/p97 functions at a post-fusion, pre-translation step in YFV entry. Together, these data support a critical role for VCP/p97 in the disassembly of incoming flavivirus nucleocapsids during a post-fusion step in virus entry.nnIMPORTANCEFlaviviruses are an important group of RNA viruses that cause significant human disease. The mechanisms by which flavivirus nucleocapsids are disassembled during virus entry remain unclear. Here we show that the yellow fever virus nucleocapsid disassembly requires the cellular Protein-disaggregating enzyme Valosin-Containing Protein, also known as p97.
Changcheng Song - One of the best experts on this subject based on the ideXlab platform.
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Valosin Containing Protein vcp p97 is capable of unfolding polyubiquitinated Proteins through its atpase domains
Biochemical and Biophysical Research Communications, 2015Co-Authors: Changcheng Song, Qing Wang, Changzheng Song, Thomas J RogersAbstract:Valosin-Containing Protein (VCP or p97) is required for the proteasomal degradation of polyubiquitinated Proteins. However, the molecular mechanism for VCP to process the polyubiquitinated Proteins remains unclear. Here, we show that VCP can unfold polyubiquitinated Proteins. It preferably unfolds the pentaubiquitin-over monoubiquin-conjugated dihydrofolate reductase (Ub5-DHFR or Ub-DHFR) in a dose dependent manner. In addition, the unfolding activity of VCP does not depend on its ATPase activity, on the contrary, ATP and its non-hydrolysable analogs suppress the unfolding of Ub5-DHFR. The structural and functional analysis showed that either D1 or D2 domain of VCP is sufficient to carry out this unfolding activity. The structure of the substrates also affects its unfolding by VCP. VCP is unable to unfold Ub5-DHFR in a tight structure when it binds with methotrexate, a folate analog with high affinity to DHFR. Thus, these results support that VCP is capable of unfolding polyubiquitinated Proteins and suggest that VCP may facilitate the proteasomal degradation of polyubiquitinated Proteins through its unfolding activity.
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Valosin-Containing Protein (VCP/p97) is capable of unfolding polyubiquitinated Proteins through its ATPase domains.
Biochemical and Biophysical Research Communications, 2015Co-Authors: Changcheng Song, Qing Wang, Changzheng Song, Thomas J RogersAbstract:Valosin-Containing Protein (VCP or p97) is required for the proteasomal degradation of polyubiquitinated Proteins. However, the molecular mechanism for VCP to process the polyubiquitinated Proteins remains unclear. Here, we show that VCP can unfold polyubiquitinated Proteins. It preferably unfolds the pentaubiquitin-over monoubiquin-conjugated dihydrofolate reductase (Ub5-DHFR or Ub-DHFR) in a dose dependent manner. In addition, the unfolding activity of VCP does not depend on its ATPase activity, on the contrary, ATP and its non-hydrolysable analogs suppress the unfolding of Ub5-DHFR. The structural and functional analysis showed that either D1 or D2 domain of VCP is sufficient to carry out this unfolding activity. The structure of the substrates also affects its unfolding by VCP. VCP is unable to unfold Ub5-DHFR in a tight structure when it binds with methotrexate, a folate analog with high affinity to DHFR. Thus, these results support that VCP is capable of unfolding polyubiquitinated Proteins and suggest that VCP may facilitate the proteasomal degradation of polyubiquitinated Proteins through its unfolding activity.
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nucleocytoplasmic shuttling of Valosin Containing Protein vcp p97 regulated by its n domain and c terminal region
Biochimica et Biophysica Acta, 2015Co-Authors: Changcheng Song, Chouchi H Li, Qing Wang, Changzheng Song, Stephen J Lockett, Nancy H Colburn, Ji Ming Wang, Thomas J RogersAbstract:Valosin-Containing Protein (VCP or p97), a member of the AAA family (ATPases associated with diverse cellular activities), plays a key role in many important cellular activities. A genetic deficiency of VCP can cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). Previous studies showed that the VCP N domain is essential for the regulation of nuclear entry of VCP. Here we report that IBMPFD mutations, which are mainly located in the N domain, suppress the nuclear entry of VCP. Moreover, the peptide sequence G780AGPSQ in the C-terminal region regulates the retention of VCP in the nucleus. A mutant lacking this sequence can increase the nuclear distribution of IBMPFD VCP, suggesting that this sequence is a potential molecular target for correcting the deficient nucleocytoplasmic shuttling of IBMPFD VCP Proteins.
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Nucleocytoplasmic shuttling of Valosin-Containing Protein (VCP/p97) regulated by its N domain and C-terminal region.
Biochimica et Biophysica Acta, 2014Co-Authors: Changcheng Song, Chouchi H Li, Qing Wang, Changzheng Song, Stephen J Lockett, Nancy H Colburn, Ji Ming Wang, Thomas J RogersAbstract:Valosin-Containing Protein (VCP or p97), a member of the AAA family (ATPases associated with diverse cellular activities), plays a key role in many important cellular activities. A genetic deficiency of VCP can cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). Previous studies showed that the VCP N domain is essential for the regulation of nuclear entry of VCP. Here we report that IBMPFD mutations, which are mainly located in the N domain, suppress the nuclear entry of VCP. Moreover, the peptide sequence G780AGPSQ in the C-terminal region regulates the retention of VCP in the nucleus. A mutant lacking this sequence can increase the nuclear distribution of IBMPFD VCP, suggesting that this sequence is a potential molecular target for correcting the deficient nucleocytoplasmic shuttling of IBMPFD VCP Proteins.
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the heavy metal cadmium induces Valosin Containing Protein vcp mediated aggresome formation
Toxicology and Applied Pharmacology, 2008Co-Authors: Changcheng Song, Chouchi H Li, Qing Wang, Stephen J Lockett, Nancy H Colburn, Zhen Xiao, Kunio Nagashima, Thomas P Conrads, Timothy D Veenstra, Ji Ming WangAbstract:Cadmium (Cd{sup 2+}) is a heavy metal ion known to have a long biological half-life in humans. Accumulating evidence shows that exposure to Cd{sup 2+} is associated with neurodegenerative diseases characterized by the retention of ubiquitinated and misfolded Proteins in the lesions. Here, we report that Cd{sup 2+} directly induces the formation of Protein inclusion bodies in cells. The Protein inclusion body is an aggresome, a major organelle for collecting ubiquitinated or misfolded Proteins. Our results show that aggresomes are enriched in the detergent-insoluble fraction of Cd{sup 2+}-treated cell lysates. Proteomic analysis identified 145 Proteins in the aggresome-enriched fractions. One of the Proteins is the highly conserved Valosin-Containing Protein (VCP), which has been shown to colocalize with aggresomes and bind ubiquitinated Proteins through its N domain (1-200). Our subsequent examination of VCP's role in the formation of aggresomes induced by Cd{sup 2+} indicates that the C-terminal tail (no. 780-806) of VCP interacts with histone deacetylase HDAC6, a mediator for aggresome formation, suggesting that VCP participates in transporting ubiquitinated Proteins to aggresomes. This function of VCP is impaired by inhibition of the deacetylase activity of HDAC6 or by over-expression of VCP mutants that do not bind ubiquitinated Proteins or HDAC6. Ourmore » results indicate that Cd{sup 2+} induces the formation of Protein inclusion bodies by promoting the accumulation of ubiquitinated Proteins in aggresomes through VCP and HDAC6. Our delineation of the role of VCP in regulating cell responses to ubiquitinated Proteins has important implications for understanding Cd{sup 2+} toxicity and associated diseases.« less
William W Hall - One of the best experts on this subject based on the ideXlab platform.
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Valosin Containing Protein vcp p97 plays a role in the replication of west nile virus
Virus Research, 2017Co-Authors: Wallaya Phongphaew, Shintaro Kobayashi, Michihito Sasaki, Michael J Carr, William W Hall, Yasuko Orba, Hirofumi SawaAbstract:Abstract Valosin-Containing Protein (VCP) is classified as a member of the type II AAA+ ATPase Protein family. VCP functions in several cellular processes, including Protein degradation, membrane fusion, vesicular trafficking and disassembly of stress granules. Moreover, VCP is considered to play a role in the replication of several viruses, albeit through different mechanisms. In the present study, we have investigated the role of VCP in West Nile virus (WNV) infection. Endogenous VCP expression was inhibited using either VCP inhibitors or by siRNA knockdown. It could be shown that the inhibition of endogenous VCP expression significantly inhibited WNV infection. The entry assay revealed that silencing of endogenous VCP caused a significant reduction in the expression levels of WNV-RNA compared to control siRNA-treated cells. This indicates that VCP may play a role in early steps either the binding or entry steps of the WNV life cycle. Using WNV virus like particles and WNV-DNA-based replicon, it could be demonstrated that perturbation of VCP expression decreased levels of newly synthesized WNV genomic RNA. These findings suggest that VCP is involved in early steps and during genome replication of the WNV life cycle.
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Valosin-Containing Protein (VCP/p97) plays a role in the replication of West Nile virus.
Virus Research, 2016Co-Authors: Wallaya Phongphaew, Shintaro Kobayashi, Michihito Sasaki, Michael J Carr, William W Hall, Yasuko Orba, Hirofumi SawaAbstract:Abstract Valosin-Containing Protein (VCP) is classified as a member of the type II AAA+ ATPase Protein family. VCP functions in several cellular processes, including Protein degradation, membrane fusion, vesicular trafficking and disassembly of stress granules. Moreover, VCP is considered to play a role in the replication of several viruses, albeit through different mechanisms. In the present study, we have investigated the role of VCP in West Nile virus (WNV) infection. Endogenous VCP expression was inhibited using either VCP inhibitors or by siRNA knockdown. It could be shown that the inhibition of endogenous VCP expression significantly inhibited WNV infection. The entry assay revealed that silencing of endogenous VCP caused a significant reduction in the expression levels of WNV-RNA compared to control siRNA-treated cells. This indicates that VCP may play a role in early steps either the binding or entry steps of the WNV life cycle. Using WNV virus like particles and WNV-DNA-based replicon, it could be demonstrated that perturbation of VCP expression decreased levels of newly synthesized WNV genomic RNA. These findings suggest that VCP is involved in early steps and during genome replication of the WNV life cycle.
Chouchi H Li - One of the best experts on this subject based on the ideXlab platform.
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nucleocytoplasmic shuttling of Valosin Containing Protein vcp p97 regulated by its n domain and c terminal region
Biochimica et Biophysica Acta, 2015Co-Authors: Changcheng Song, Chouchi H Li, Qing Wang, Changzheng Song, Stephen J Lockett, Nancy H Colburn, Ji Ming Wang, Thomas J RogersAbstract:Valosin-Containing Protein (VCP or p97), a member of the AAA family (ATPases associated with diverse cellular activities), plays a key role in many important cellular activities. A genetic deficiency of VCP can cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). Previous studies showed that the VCP N domain is essential for the regulation of nuclear entry of VCP. Here we report that IBMPFD mutations, which are mainly located in the N domain, suppress the nuclear entry of VCP. Moreover, the peptide sequence G780AGPSQ in the C-terminal region regulates the retention of VCP in the nucleus. A mutant lacking this sequence can increase the nuclear distribution of IBMPFD VCP, suggesting that this sequence is a potential molecular target for correcting the deficient nucleocytoplasmic shuttling of IBMPFD VCP Proteins.
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Nucleocytoplasmic shuttling of Valosin-Containing Protein (VCP/p97) regulated by its N domain and C-terminal region.
Biochimica et Biophysica Acta, 2014Co-Authors: Changcheng Song, Chouchi H Li, Qing Wang, Changzheng Song, Stephen J Lockett, Nancy H Colburn, Ji Ming Wang, Thomas J RogersAbstract:Valosin-Containing Protein (VCP or p97), a member of the AAA family (ATPases associated with diverse cellular activities), plays a key role in many important cellular activities. A genetic deficiency of VCP can cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). Previous studies showed that the VCP N domain is essential for the regulation of nuclear entry of VCP. Here we report that IBMPFD mutations, which are mainly located in the N domain, suppress the nuclear entry of VCP. Moreover, the peptide sequence G780AGPSQ in the C-terminal region regulates the retention of VCP in the nucleus. A mutant lacking this sequence can increase the nuclear distribution of IBMPFD VCP, suggesting that this sequence is a potential molecular target for correcting the deficient nucleocytoplasmic shuttling of IBMPFD VCP Proteins.
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the heavy metal cadmium induces Valosin Containing Protein vcp mediated aggresome formation
Toxicology and Applied Pharmacology, 2008Co-Authors: Changcheng Song, Chouchi H Li, Qing Wang, Stephen J Lockett, Nancy H Colburn, Zhen Xiao, Kunio Nagashima, Thomas P Conrads, Timothy D Veenstra, Ji Ming WangAbstract:Cadmium (Cd{sup 2+}) is a heavy metal ion known to have a long biological half-life in humans. Accumulating evidence shows that exposure to Cd{sup 2+} is associated with neurodegenerative diseases characterized by the retention of ubiquitinated and misfolded Proteins in the lesions. Here, we report that Cd{sup 2+} directly induces the formation of Protein inclusion bodies in cells. The Protein inclusion body is an aggresome, a major organelle for collecting ubiquitinated or misfolded Proteins. Our results show that aggresomes are enriched in the detergent-insoluble fraction of Cd{sup 2+}-treated cell lysates. Proteomic analysis identified 145 Proteins in the aggresome-enriched fractions. One of the Proteins is the highly conserved Valosin-Containing Protein (VCP), which has been shown to colocalize with aggresomes and bind ubiquitinated Proteins through its N domain (1-200). Our subsequent examination of VCP's role in the formation of aggresomes induced by Cd{sup 2+} indicates that the C-terminal tail (no. 780-806) of VCP interacts with histone deacetylase HDAC6, a mediator for aggresome formation, suggesting that VCP participates in transporting ubiquitinated Proteins to aggresomes. This function of VCP is impaired by inhibition of the deacetylase activity of HDAC6 or by over-expression of VCP mutants that do not bind ubiquitinated Proteins or HDAC6. Ourmore » results indicate that Cd{sup 2+} induces the formation of Protein inclusion bodies by promoting the accumulation of ubiquitinated Proteins in aggresomes through VCP and HDAC6. Our delineation of the role of VCP in regulating cell responses to ubiquitinated Proteins has important implications for understanding Cd{sup 2+} toxicity and associated diseases.« less
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characterization of the aggregation prevention activity of p97 Valosin Containing Protein
Biochemistry, 2007Co-Authors: Changcheng Song, Qing Wang, Chouchi H LiAbstract:The 97 kDa Valosin-Containing Protein (VCP) belongs to a highly conserved AAA (ATPases associated with a variety of activities) family and contains two ATPase domains, D1 and D2. VCP participates in numerous cellular activities, such as membrane fusion, postmitotic Golgi reassembly, endoplasmic reticulum-associated degradation, ubiquitin−proteasome-mediated proteolysis, and many others. In performing these activities, VCP presumably acts as a molecular chaperone that prevents Protein aggregation and modifies Protein conformation. In this study, we characterized the aggregation-prevention activity of VCP and identified the structural requirement for this activity. We used multiple methods to treat aggregation-prone luciferase (Luc) and showed that VCP prevents the aggregation of Luc in vitro. These results are in agreement; in vivo RNA interference analyses showed that a reduction of VCP level results in more aggregation of Luc in cells. Structural and functional analyses further demonstrated that the D1 d...
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Characterization of the aggregation-prevention activity of p97/Valosin-Containing Protein.
Biochemistry, 2007Co-Authors: Changcheng Song, Qing Wang, Chouchi H LiAbstract:The 97 kDa Valosin-Containing Protein (VCP) belongs to a highly conserved AAA (ATPases associated with a variety of activities) family and contains two ATPase domains, D1 and D2. VCP participates in numerous cellular activities, such as membrane fusion, postmitotic Golgi reassembly, endoplasmic reticulum-associated degradation, ubiquitin−proteasome-mediated proteolysis, and many others. In performing these activities, VCP presumably acts as a molecular chaperone that prevents Protein aggregation and modifies Protein conformation. In this study, we characterized the aggregation-prevention activity of VCP and identified the structural requirement for this activity. We used multiple methods to treat aggregation-prone luciferase (Luc) and showed that VCP prevents the aggregation of Luc in vitro. These results are in agreement; in vivo RNA interference analyses showed that a reduction of VCP level results in more aggregation of Luc in cells. Structural and functional analyses further demonstrated that the D1 d...
