The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP

  1. Maria Körner
  2. Susanne R Meyer
  3. Gabriella Marincola
  4. Maximilian J Kern
  5. Clemens Grimm
  6. Christina Schuelein-Voelk
  7. Utz Fischer
  8. Kay Hofmann
  9. Alexander Buchberger  Is a corresponding author
  1. University of Würzburg, Germany
  2. Max Planck Institute of Biochemistry, Germany
  3. University of Cologne, Germany

Abstract

The ATPase p97 (also known as VCP, Cdc48) has crucial functions in a variety of important cellular processes such as protein quality control, organellar homeostasis and DNA damage repair, and its de-regulation is linked to neuro-muscular diseases and cancer. p97 is tightly controlled by numerous regulatory cofactors, but the full range and function of the p97-cofactor network is unknown. Here, we identify the hitherto uncharacterized FAM104 proteins as a conserved family of p97 interactors. The two human family members VCP nuclear cofactor family member 1 and 2 (VCF1/2) bind p97 directly via a novel, alpha-helical motif and associate with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells. VCF1/2 localize to the nucleus and promote the nuclear import of p97. Loss of VCF1/2 results in reduced nuclear p97 levels, slow growth and hypersensitivity to chemical inhibition of p97 in the absence and presence of DNA damage, suggesting that FAM104 proteins are critical regulators of nuclear p97 functions.

Data availability

All data analysed during this study are included in the manuscript and supporting files; Source Data files will be made available before publication.

Article and author information

Author details

  1. Maria Körner

    Chair of Biochemistry I, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Susanne R Meyer

    Chair of Biochemistry I, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Gabriella Marincola

    Chair of Biochemistry I, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9227-6554
  4. Maximilian J Kern

    Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Clemens Grimm

    Chair of Biochemistry I, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Christina Schuelein-Voelk

    Core Unit High-Content Microscopy, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Utz Fischer

    Chair of Biochemistry I, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1465-6591
  8. Kay Hofmann

    Institute of Genetics, University of Cologne, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2289-9083
  9. Alexander Buchberger

    Chair of Biochemistry I,, University of Würzburg, Würzburg, Germany
    For correspondence
    alexander.buchberger@uni-wuerzburg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2836-0820

Funding

Deutsche Forschungsgemeinschaft (GRK2243/1+2)

  • Maria Körner

Deutsche Forschungsgemeinschaft (INST 93/1023-1-FUGG)

  • Christina Schuelein-Voelk

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. David Ron, University of Cambridge, United Kingdom

Version history

  1. Received: September 3, 2023
  2. Accepted: September 10, 2023
  3. Accepted Manuscript published: September 15, 2023 (version 1)

Copyright

© 2023, Körner et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Maria Körner
  2. Susanne R Meyer
  3. Gabriella Marincola
  4. Maximilian J Kern
  5. Clemens Grimm
  6. Christina Schuelein-Voelk
  7. Utz Fischer
  8. Kay Hofmann
  9. Alexander Buchberger
(2023)
The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP
eLife 12:e92409.
https://doi.org/10.7554/eLife.92409

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