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AlphaFold2-Guided Functional Screens Reveal a Conserved Antioxidant Protein at ER Membranes
Zhijian Ji1, Taruna Pandey1, Henry de Belly1,2
1Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA.
Biorxiv : the Preprint Server for Biology
|July 1, 2024
Summary
Researchers discovered ERGU-1, an endoplasmic reticulum (ER) membrane protein crucial for managing hydrogen peroxide (H2O2) and maintaining cellular antioxidant defense. This conserved protein is vital for organismal health and H2O2 responses.
Area of Science:
- Cellular Biology
- Biochemistry
- Genetics
Background:
- Oxidative protein folding in the endoplasmic reticulum (ER) generates hydrogen peroxide (H2O2), a reactive oxygen species (ROS).
- The specific ER-transmembrane protein responsible for providing reducing equivalents and cytosolic antioxidant defense remained unidentified.
Purpose of the Study:
- To identify and characterize a novel ER-transmembrane protein involved in peroxide detoxification and antioxidant defense.
- To elucidate the evolutionary conservation and functional roles of this protein in cellular and organismal responses to H2O2.
Main Methods:
- Utilized AlphaFold2-based and functional reporter screens in *C. elegans*.
- Performed gene deletion studies to analyze phenotypes associated with ERGU-1 deficiency.
- Investigated protein localization, oligomeric states, and cross-species rescue experiments.
Main Results:
- Discovered and characterized ERGU-1, an evolutionarily conserved ER-membrane protein.
- ERGU-1 deletion led to excessive H2O2, SKN-1/NRF2 pathway activation, and impaired reproductive/behavioral responses.
- ERGU-1 homologs in humans and *Drosophila* rescued *C. elegans* mutant phenotypes, confirming conserved functions.
Conclusions:
- ERGU-1 functions as a peroxide detoxification machinery at the ER membrane.
- Identified a novel, conserved mechanism for antioxidant defense in animal cells involving ER-membrane proteins.
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