ArticleProceedings of the National Academy of Sciences of the United States of America2017
Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 127 papers.
What it found
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Who cites it
127 citing papers in PubMed, 180 citations in OpenAlex.
- ATP-independent unfolding of ubiquitin by Ufd1 initiates Cdc48/p97-mediated substrate processing.Nature structural & molecular biology · 2026Article
- Cyclin D-CDK4/6 couple proliferation to membrane and mitochondrial protein supply through a DeSI1 phospho-switch.bioRxiv : the preprint server for biology · 2026Article
- FAF1 and FAF2 enhance unfolding by p97-UFD1-NPL4 complex enabling rational design of p97 activators.The EMBO journal · 2026Article
- Stimulating proteasomal degradation in human proteinopathies.The FEBS journal · 2026Review
- FAF1 cofactor enhances UFD1/NPL4-p97 unfolding efficiency across ubiquitin chain lengths independent of SUMO2.bioRxiv : the preprint server for biology · 2026Article
- Faf1 accelerates p97-mediated protein unfolding by promoting ubiquitin engagement.Cell reports · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.Research square · 2026Article
- ASPL-driven subunit exchange remodels VCP/p97 hexamers and is impaired by a multisystem proteinopathy mutation.bioRxiv : the preprint server for biology · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.bioRxiv : the preprint server for biology · 2026Article
- Direct observation of ATP-driven ubiquitin chain handling by Cdc48.Nature communications · 2026Article
- The accessory adapters FAF1, FAF2, and UBXN7 accelerate proteasomal degradation by increasing prior p97-mediated substrate unfolding.Science advances · 2026Article
- Stress granules as a central hub linking organelle stress, aging, and neurodegeneration.BMB reports · 2026Review
- NPLOC4 Constructs Tumor Immunosuppressive Microenvironment in Pan-cancer and Hepatocellular Carcinoma.Current medicinal chemistry · 2026Article
- A Multi-Omics Study of Comorbid Mechanisms Between Depression and Inflammatory Dermatoses Identifies FADS1 and TMEM258 as Therapeutic Targets.Clinical, cosmetic and investigational dermatology · 2026Article
- A UBH-UBX module amplifies p97/VCP's unfolding power to facilitate protein extraction and degradation.Nature communications · 2025Article
- HSAInternational journal of molecular sciences · 2025Article
- Faf1 accelerates p97-mediated protein unfolding by promoting ubiquitin engagement.bioRxiv : the preprint server for biology · 2025Article
- Dynamic regulation of the oxidative stress response by the E3 ligase TRIP12.Cell reports · 2025Article
- Ribosome biogenesis in plants requires the nuclear envelope and mitochondria localized OPENER complex.Nature communications · 2025Article
- Site-directed multivalent conjugation of antibodies to ubiquitinated payloads.Nature biomedical engineering · 2025Article
67 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
p97 is a "segregase" that plays a key role in numerous ubiquitin (Ub)-dependent pathways such as ER-associated degradation. It has been hypothesized that p97 extracts proteins from membranes or macromolecular complexes to enable their proteasomal degradation; however, the complex nature of p97 substrates has made it difficult to directly observe the fundamental basis for this activity. To address this issue, we developed a soluble p97 substrate-Ub-GFP modified with K48-linked ubiquitin chains-for in vitro p97 activity assays. We demonstrate that WT p97 can unfold proteins and that this activity is dependent on the p97 adaptor NPLOC4-UFD1L, ATP hydrolysis, and substrate ubiquitination, with branched chains providing maximal stimulation. Furthermore, we show that a p97 mutant that causes inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia in humans unfolds substrate faster, suggesting that excess activity may underlie pathogenesis. This work overcomes a significant barrier in the study of p97 and will allow the future dissection of p97 mechanism at a level of detail previously unattainable.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.