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

Author

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  • Yihong Ye

    (Harvard Medical School)

  • Hemmo H. Meyer

    (Yale Medical School)

  • Tom A. Rapoport

    (Harvard Medical School)

Abstract

In eukaryotic cells, incorrectly folded proteins in the endoplasmic reticulum (ER) are exported into the cytosol and degraded by the proteasome1. 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 degradation2. 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 proteins3,4. 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 fusion6,7,8, 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.

Suggested Citation

  • Yihong Ye & Hemmo H. Meyer & Tom A. Rapoport, 2001. "The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol," Nature, Nature, vol. 414(6864), pages 652-656, December.
    • Handle: RePEc:nat:nature:v:414:y:2001:i:6864:d:10.1038_414652a
    DOI: 10.1038/414652a
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    Cited by:

    1. Liangguang Leo Lin & Huilun Helen Wang & Brent Pederson & Xiaoqiong Wei & Mauricio Torres & You Lu & Zexin Jason Li & Xiaodan Liu & Hancheng Mao & Hui Wang & Linyao Elina Zhou & Zhen Zhao & Shengyi Su, 2024. "SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Kevin Wu & Samuel Itskanov & Diane L. Lynch & Yuanyuan Chen & Aasha Turner & James C. Gumbart & Eunyong Park, 2024. "Substrate recognition mechanism of the endoplasmic reticulum-associated ubiquitin ligase Doa10," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Wenjing Yan & Yongwang Zhong & Xin Hu & Tuan Xu & Yinghua Zhang & Stephen Kales & Yanyan Qu & Daniel C. Talley & Bolormaa Baljinnyam & Christopher A. LeClair & Anton Simeonov & Brian M. Polster & Ruil, 2023. "Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Ya-Chu Chang & Yu-Xiang Peng & Bo-Hua Yu & Henry C. Chang & Pei-Shin Liang & Ting-Yi Huang & Chao-Jie Shih & Li-An Chu & Tzu-Kang Sang, 2021. "VCP maintains nuclear size by regulating the DNA damage-associated MDC1–p53–autophagy axis in Drosophila," Nature Communications, Nature, vol. 12(1), pages 1-17, December.

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