Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction
- University of Utah, United States
- University of Toledo, United States
- Whitehead Institute for Biomedical Research, United States
- Dana-Farber Cancer Institute, United States
- 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
Matthew L Wohlever
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.
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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Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction
eLife 11:e82860.
https://doi.org/10.7554/eLife.82860
Further reading
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- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
In the bacterium M. smegmatis, an enzyme called MftG allows the cofactor mycofactocin to transfer electrons released during ethanol metabolism to the electron transport chain.
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- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- and ATP-dependent LLPSs of an IDR of messenger RNA-regulating protein Caprin1 and its phosphorylated variant pY-Caprin1, exhibiting, for example, reentrant behaviors in some instances but not others. Experimental data are rationalized by physical modeling using analytical theory, molecular dynamics, and polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS of polyelectrolytes such as Caprin1 and the high valency of ATP-magnesium is a significant factor for its colocalization with the condensed phases, as similar trends are observed for other IDRs. The electrostatic nature of these features complements ATP’s involvement in π-related interactions and as an amphiphilic hydrotrope, underscoring a general role of biomolecular condensates in modulating ion concentrations and its functional ramifications.
