Structural basis and regulation of the reductive stress response.
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 CUL2FEM1B can bind its target based on redox state and how this is adjusted to changing cellular environments. Here, we show that CUL2FEM1B 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.
Mesh Terms:
Amino Acids, Animals, Carrier Proteins, Cell Cycle Proteins, Cell Line, Female, Humans, Ions, Mice, Mutant Proteins, Mutation, Protein Binding, Protein Stability, Reactive Oxygen Species, Stress, Physiological, Structure-Activity Relationship, Substrate Specificity, Ubiquitin-Protein Ligase Complexes, Ubiquitination, Zinc
Amino Acids, Animals, Carrier Proteins, Cell Cycle Proteins, Cell Line, Female, Humans, Ions, Mice, Mutant Proteins, Mutation, Protein Binding, Protein Stability, Reactive Oxygen Species, Stress, Physiological, Structure-Activity Relationship, Substrate Specificity, Ubiquitin-Protein Ligase Complexes, Ubiquitination, Zinc
Cell
Date: Dec. 14, 2020
PubMed ID: 34562363
View in: Pubmed Google Scholar
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