The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol

Ye, Yihong; Meyer, Hemmo H.; Rapoport, Tom A.

doi:10.1038/414652a

Cited by 1,099Ubiquitin and proteasome pathwaysHeat shock proteins researchEndoplasmic Reticulum Stress and Disease

The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol

Ye, Yihong, Meyer, Hemmo H., Rapoport, Tom A.·2001·Nature

DOI 10.1038/414652a

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Abstract

In eukaryotic cells, incorrectly folded proteins in the endoplasmic reticulum (ER) are exported into the cytosol and degraded by the proteasome. This pathway is co-opted by some viruses. For example, the US11 protein of the human cytomegalovirus targets the major histocompatibility complex class I heavy chain for cytosolic degradation. How proteins are extracted from the ER membrane is unknown. In bacteria and mitochondria, members of the AAA ATPase family are involved in extracting and degrading membrane proteins. Here we demonstrate that another member of this family, Cdc48 in yeast and p97 in mammals, is required for the export of ER proteins into the cytosol. Whereas Cdc48/p97 was previously known to function in a complex with the cofactor p47 (ref. 5) in membrane fusion, we demonstrate that its role in ER protein export requires the interacting partners Ufd1 and Npl4. The AAA ATPase interacts with substrates at the ER membrane and is needed to release them as polyubiquitinated species into the cytosol. We propose that the Cdc48/p97-Ufd1-Npl4 complex extracts proteins from the ER membrane for cytosolic degradation.

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During ER stress, misfolded proteins accumulate in the ER lumen and are retrotranslocated into the cytosol, ubiquitinated, and degraded by the proteasome in ER-associated protein degradation (ERAD).
“During ER stress, misfolded proteins accumulate into the ER lumen. They need to be retrotranslocated into the cytosol, where they are flagged with ubiquitin and degraded by the proteasome in a process called ER-associated protein degradation (ERAD) [47].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [47]
p97/VCP is critical in the retrotranslocation and degradation of endoplasmic reticulum-associated proteins (ERAD) and mitochondrial proteins (MAD).
“p97/VCP is critical in the retrotranslocation and degradation of endoplasmic reticulum-associated proteins (ERAD) [47] and mitochondrial proteins ( MAD) [49, 50].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [47]

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Authors: Ye, Y., Meyer, H. H., & Rapoport, T. A.
Affiliations: Howard Hughes Medical Institute (US)
Yale University (US)
Corresponding author: Rapoport, Tom A.
ORCID: Ye, Yihong
Meyer, Hemmo H.
Rapoport, Tom A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2001-12-06
Volume: 414
Issue: 6864
Pages: 652-656
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/414652a
OpenAlex: W2033088972
Cited by: 1,099
References: 30
Citations by year: 2026: 16 · 2025: 16 · 2024: 32 · 2023: 34 · 2022: 26 · 2021: 31 · 2020: 41 · 2019: 40 · 2018: 42 · 2017: 39 · 2016: 51 · 2015: 37 · 2014: 40 · 2013: 59 · 2012: 59
FWCI: 16.41
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health
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 › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords: Cdc48/p97, AAA+ ATPase, Ufd1, Npl4, polyubiquitination, proteasome, misfolded proteins, MHC class I heavy chain, membrane fusion, yeast, mammalian cells
MeSH terms: Valosin Containing Protein, Adenosine Triphosphatases, Animals, Carboxypeptidases, Carrier Proteins, Cytosol, Endoplasmic Reticulum, H-2 Antigens, Membrane Proteins, Mutation, Nuclear Proteins, Proteins, Saccharomyces cerevisiae, Tumor Cells, Cultured, Histocompatibility Antigens Class I, Protein Folding, Cell Cycle Proteins, Protein Transport, Nuclear Pore Complex Proteins, Nucleocytoplasmic Transport Proteins, Saccharomyces cerevisiae Proteins, Vesicular Transport Proteins, Adaptor Proteins, Vesicular Transport, Cathepsin A, Intracellular Signaling Peptides and Proteins, Rats, Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins

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The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol

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