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PreprintCited by 37Ubiquitin and proteasome pathwaysHeat shock proteins researchDNA Repair Mechanisms

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Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase

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Fujisawa, Ryo, Labib, Karim P.M.·2022·eLife
DOI 10.1101/2022.01.13.476277PMC PMC9377798

Preprint — published as 10.7554/elife.76763 · Paper page

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Abstract

The unfolding of ubiquitylated proteins by the p97 / Cdc48 ATPase and its ubiquitin receptors Ufd1-Npl4 is essential in many areas of eukaryotic cell biology. Previous studies showed that yeast Cdc48-Ufd1-Npl4 is governed by a quality control mechanism, whereby substrates must be conjugated to at least five ubiquitins. Here we show that substrate processing by mammalian p97-UFD1-NPL4 involves a complex interplay between ubiquitin chain length and additional p97 cofactors. Using disassembly of the ubiquitylated CMG helicase as a model in vitro system, we find that reconstituted p97-UFD1-NPL4 only unfolds substrates with very long ubiquitin chains. However, this high ubiquitin threshold is greatly reduced, to a level resembling yeast Cdc48-Ufd1-Npl4, by the UBXN7, FAF1 or FAF2 partners of mammalian p97-UFD1-NPL4. Stimulation by UBXN7/FAF1/FAF2 requires the UBX domain that connects each factor to p97, together with the ubiquitin-binding UBA domain of UBXN7 and a previously uncharacterised coiled-coil domain in FAF1/FAF2. Furthermore, we show that deletion of the UBXN7 and FAF1 genes impairs CMG disassembly during S-phase and mitosis and sensitises cells to reduced ubiquitin ligase activity. These findings indicate that multiple UBX proteins are important for the efficient unfolding of ubiquitylated proteins by p97-UFD1-NPL4 in mammalian cells.

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Metadata

Authors
Fujisawa, R., & Labib, K. P. M.
Affiliations
Harvard University (US)
Corresponding author
Labib, Karim P.M.
ORCID
Venue
eLife
Publisher
openRxiv
Published
2022-01-14
Volume
11
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2022.01.13.476277
PMC
PMC9377798
OpenAlex
W4289550428
Cited by
37
References
1
Citations by year
2026: 11 · 2025: 4 · 2024: 8 · 2023: 11 · 2022: 3
FWCI
2.12
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Cancer Research UK (24558, C578/A24558, S_3994, C578/A25671)
  • Medical Research Council Canada (MC_UU_12016/13)
  • Medical Research Council (MC_UU_12016/13, MC_UU_12016, MC_UU_00018/4)
  • Japan Society for the Promotion of Science (202160572)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
FAF1, ubiquitin receptors, K48-linked ubiquitin chains, protein unfolding, coiled-coil domain, ubiquitin ligase, S phase, mitosis, protein quality control
MeSH terms
Valosin Containing Protein, Animals, Humans, Nuclear Proteins, Protein Binding, Ubiquitins, Cell Cycle Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins

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