ArticleThe Journal of biological chemistry2016
Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 63 citations in OpenAlex.
- The long road to diagnosis: recessive PMPCB deficiency hidden behind a dominant familial VCP defect.Molecular genetics and metabolism reports · 2026Article
- ASPL-driven subunit exchange remodels VCP/p97 hexamers and is impaired by a multisystem proteinopathy mutation.bioRxiv : the preprint server for biology · 2026Article
- Direct observation of ATP-driven ubiquitin chain handling by Cdc48.Nature communications · 2026Article
- Organelle regulation of SUMOylation: regulatory mechanisms and therapeutic application.Journal of advanced research · 2026Review
- The VCPKMT-VCP-HDAC1 axis inhibits colorectal cancer by conferring sensitivity to ferroptosis.Cancer cell international · 2025Article
- Harnessing p97/VCP: A Transformative AAA+ ATPase Target for Next-Generation Cancer Therapeutics.Cancers · 2025Review
- Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes.International journal of molecular sciences · 2024Review
- Paralogue-Specific Roles of SUMO1 and SUMO2/3 in Protein Quality Control and Associated Diseases.Cells · 2023Review
- Phosphoproteome analysis of the crosstalk between sumoylation and phosphorylation in mouse spermatocytes.Biochemical and biophysical research communications · 2023Article
- An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP.American journal of human genetics · 2023Article
- Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases.Molecular neurodegeneration · 2023Review
- A New Phase of Networking: The Molecular Composition and Regulatory Dynamics of Mammalian Stress Granules.Chemical reviews · 2023Review
- Is bRaQCing bad? New roles for ribosome associated quality control factors in stress granule regulation.Biochemical Society transactions · 2022Article
- A SUMO4 initiator codon variant in amyotrophic lateral sclerosis reduces SUMO4 expression and alters stress granule dynamics.Journal of neurology · 2022Article
- The Role of Ubiquitin in Regulating Stress Granule Dynamics.Frontiers in physiology · 2022Review
- Phenotype of VCP Mutations in Chinese Amyotrophic Lateral Sclerosis Patients.Frontiers in neurology · 2022Article
- Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation.iScience · 2021Article
- SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution.Molecular neurobiology · 2021Article
- Emerging role of VCP/p97 in cardiovascular diseases: novel insights and therapeutic opportunities.Biochemical Society transactions · 2021Review
- The UFM1 Pathway Impacts HCMV US2-Mediated Degradation of HLA Class I.Molecules (Basel, Switzerland) · 2021Article
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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