Structural basis and regulation of the reductive stress response
Open accessAbstract
Although oxidative phosphorylation is best known for producing ATP, it also yields reactive oxygen species (ROS) as invariant byproducts. Depletion of ROS below their physiological levels, a phenomenon known as reductive stress, impedes cellular signaling and has been linked to cancer, diabetes, and cardiomyopathy. Cells alleviate reductive stress by ubiquitylating and degrading the mitochondrial gatekeeper FNIP1, yet it is unknown how the responsible E3 ligase CUL2 FEM1B can bind its target based on redox state and how this is adjusted to changing cellular environments. Here, we show that CUL2 FEM1B relies on zinc as a molecular glue to selectively recruit reduced FNIP1 during reductive stress. FNIP1 ubiquitylation is gated by pseudosubstrate inhibitors of the BEX family, which prevent premature FNIP1 degradation to protect cells from unwarranted ROS accumulation. FEM1B gain-of-function mutation and BEX deletion elicit similar developmental syndromes, showing that the zinc-dependent reductive stress response must be tightly regulated to maintain cellular and organismal homeostasis.
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CUL2 FEM1B relies on Zn2+ ions as molecular glues to selectively recruit reduced FNIP1 during reductive stress.
“Recently reported in mammalian cells by the Rape lab, CUL2 FEM1B relies on Zn 2+ ions as ''MGs'' to selectively recruit reduced FNIP1 (and not oxidized FNIP1) during reductive stress, thereby explaining how an E3 ligase can discriminate targets based on redox state.102”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [102]
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Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications
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Self-citationChasing molecular glue degraders: screening approaches
Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., & Mayor-Ruiz, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00197g · Cited by 200 · see citing works
Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations
Xie, X., Zhang, O., Yeo, M. J. R., Lee, C., Tao, R., Harry, S. A., Payne, N. C., Nam, E., Paul, L., Li, Y., et al. (2025) · Nature · doi:10.1038/s41586-024-08533-3 · Cited by 50 · see citing works
From serendipity to strategy: molecular glue degraders in cancer therapeutics
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“…elements can serve as molecular glues; zinc ions enable the cRl2 FeM1B e3 complex to selectively recruit new substrates during reductive stress (Manford et al. 2021). viruses, including Hiv and HPv, have also employed this strategy in mammalian cells as they use both peptides and nucleotides…”
- Authors
- Manford, A. G., Mena, E. L., Shih, K. Y., Gee, C. L., McMinimy, R., Martínez-González, B., Sherriff, R., Lew, B., Zoltek, M., Rodríguez-Pérez, F., Woldesenbet, M., Kuriyan, J., & Rape, M.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, Berkeley (US)
- QB3 (US)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 184
- Issue
- 21
- Pages
- 5375-5390.e16
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8810291
- OpenAlex
- W3202044524
- Cited by
- 152
- References
- 88
- Citations by year
- 2026: 29 · 2025: 39 · 2024: 32 · 2023: 33 · 2022: 18 · 2021: 1
- FWCI
- 6.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Biological and Environmental Research
- U.S. Department of Energy
- University of California Berkeley
- American Cancer Society (PF-15-215-01-DCC)
- National Institute of General Medical Sciences (P30GM133894)
- National Science Foundation
- Basic Energy Sciences (DE-AC02-76SF00515)
- Office of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- reductive stress, reactive oxygen species, FNIP1, E3 ubiquitin ligase, mitochondrial redox signaling, oxidative phosphorylation, protein degradation, developmental syndromes
- MeSH terms
- Amino Acids, Animals, Carrier Proteins, Cell Line, Female, Humans, Ions, Mutation, Protein Binding, Stress, Physiological, Structure-Activity Relationship, Substrate Specificity, Zinc, Reactive Oxygen Species, Cell Cycle Proteins, Ubiquitin-Protein Ligase Complexes, Mutant Proteins, Mice, Ubiquitination, Protein Stability
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