Abstract
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.
Highlights
Mitochondria possess crucial roles in metabolism and signaling that ensure tissue formation and homeostasis (Chandel, 2015; Spinelli and Haigis, 2018; Tan and Finkel, 2020)
To reveal the molecular basis of this signaling circuit, we identified a FEM1B construct with six annotated ankyrin repeats and one TPR repeat that was sufficient to capture the FNIP1 degron (Figure S1A)
We purified the complex between this FEM1B construct and a 30-residue FNIP1 degron to homogeneity (Figure S1B) and determined its X-ray crystal structure to a resolution of 2.9 A (Figures 1A and S1C–S1G; Table S1)
Summary
Mitochondria possess crucial roles in metabolism and signaling that ensure tissue formation and homeostasis (Chandel, 2015; Spinelli and Haigis, 2018; Tan and Finkel, 2020). Mutations in components of the electron transport chain, abrupt changes in the rate of oxidative phosphorylation, or environmental toxins can increase ROS to levels that damage proteins, lipids, or DNA (Sies et al, 2017). If unmitigated, such oxidative stress exhausts stem cell populations, accelerates aging, and results in cancer or neurodegeneration (Corenblum et al, 2016; Ito et al, 2004; Papa et al, 2019; Suda et al, 2011). Inhibition of CUL3KEAP1 prevents the degradation of the transcription factor NRF2 and thereby instigates an antioxidant gene expression program
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