Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction

  1. Jacob M Winter
  2. Heidi L Fresenius
  3. Corey N Cunningham
  4. Peng Wei
  5. Heather R Keys
  6. Jordan A Berg
  7. Alex J Bott
  8. Tarun Yadav
  9. Jeremy A Ryan
  10. Deepika Sirohi
  11. Sheryl R Tripp
  12. Paige Barta
  13. Neeraj Agarwal
  14. Anthony Letai
  15. David M Sabatini
  16. Matthew L Wohlever
  17. Jared Rutter  Is a corresponding author
  1. University of Utah, United States
  2. University of Toledo, United States
  3. Whitehead Institute for Biomedical Research, United States
  4. Dana-Farber Cancer Institute, United States
  5. Massachusetts Institute of Technology, United States

Abstract

The tumor suppressor gene PTEN is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of PTEN itself, which frequently disrupts adjacent genes. Coincidental loss of PTEN-adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here we describe how the loss of ATAD1, which is adjacent to and frequently co-deleted with PTEN, predisposes cancer cells to apoptosis triggered by proteasome dysfunction and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic protein BIM from mitochondria to inactivate it. Cultured cells and mouse xenografts lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which activate BIM and trigger apoptosis. This work furthers our understanding of mitochondrial protein homeostasis and could lead to new therapeutic options for the hundreds of thousands of cancer patients who have tumors with chromosome 10q23 deletion.

Data availability

All data and source data generated or analyzed are included as supplementary files. CRISPR screening data and human mCRPC survival data are provided as supplementary files.

Article and author information

Author details

  1. Jacob M Winter

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    Jacob M Winter, has filed a patent related to this work. Reference: WO2021/257910.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7152-183X
  2. Heidi L Fresenius

    Department of Chemistry and Biochemistry, University of Toledo, Toledo, United States
    Competing interests
    No competing interests declared.
  3. Corey N Cunningham

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  4. Peng Wei

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  5. Heather R Keys

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1371-2288
  6. Jordan A Berg

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  7. Alex J Bott

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2273-8922
  8. Tarun Yadav

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  9. Jeremy A Ryan

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3327-1283
  10. Deepika Sirohi

    ARUP Laboratories, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  11. Sheryl R Tripp

    ARUP Laboratories, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  12. Paige Barta

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  13. Neeraj Agarwal

    Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  14. Anthony Letai

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  15. David M Sabatini

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  16. Matthew L Wohlever

    Department of Chemistry and Biochemistry, University of Toledo, Toledo, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9406-3410
  17. Jared Rutter

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    For correspondence
    rutter@biochem.utah.edu
    Competing interests
    Jared Rutter, has filed a provisional patent related to this work, reference: WO2021/257910 which focuses on using ATAD1 status as a biomarker for proteasome inhibitor therapy in cancer..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2710-9765

Funding

National Institutes of Health (1F30CA243440)

  • Jacob M Winter

Howard Hughes Medical Institute

  • Jared Rutter

National Institutes of Health (1T32DK11096601)

  • Jordan A Berg

National Institutes of Health (1F99CA253744)

  • Jordan A Berg

National Institutes of Health (5T32DK091317)

  • Corey N Cunningham

National Institutes of Health (1F32GM140525)

  • Corey N Cunningham

National Institutes of Health (K00CA212445)

  • Alex J Bott

National Institutes of Health (R35GM137904)

  • Matthew L Wohlever

National Institutes of Health (CA228346)

  • Jared Rutter

National Institutes of Health (R35GM131854)

  • Jared Rutter

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

Ethics

Animal experimentation: All of the animals were handled according to approved institutional animal care and use committee (IACUC protocol # 18-11004) protocols of the University of Utah. Every effort was made to minimize suffering.

Reviewing Editor

  1. Erica A Golemis, Fox Chase Cancer Center, United States

Publication history

  1. Received: August 20, 2022
  2. Accepted: November 20, 2022
  3. Accepted Manuscript published: November 21, 2022 (version 1)

Copyright

© 2022, Winter 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. Jacob M Winter
  2. Heidi L Fresenius
  3. Corey N Cunningham
  4. Peng Wei
  5. Heather R Keys
  6. Jordan A Berg
  7. Alex J Bott
  8. Tarun Yadav
  9. Jeremy A Ryan
  10. Deepika Sirohi
  11. Sheryl R Tripp
  12. Paige Barta
  13. Neeraj Agarwal
  14. Anthony Letai
  15. David M Sabatini
  16. Matthew L Wohlever
  17. Jared Rutter
(2022)
Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction
eLife 11:e82860.
https://doi.org/10.7554/eLife.82860

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