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Organ-specific electrophile responsivity mapping in live C. elegans.

Jinmin Liu1, Amogh Kulkarni2, Yong-Qi Gao3

  • 1Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK; Swiss Federal Institute of Technology Lausanne, Lausanne 1015, Switzerland.

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Summary

This study introduces a new method to map organ-specific electrophile responses in live organisms. It reveals how specific proteins sense and respond to electrophiles, influencing organ function and metabolite signaling.

Keywords:
4-hydroxynonenalC. eleganscytochrome P450function-guided spatial mappingorgan-specific responsivity profilingproximity labeling proteomicsreactive metabolite signalingtissue-specific stress response

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Systems Biology

Background:

  • Proximity labeling methods are restricted to identifying localized proteins.
  • Existing techniques cannot assess small-molecule responsiveness in specific cellular compartments.

Purpose of the Study:

  • To develop and validate a method for quantitatively mapping electrophile-sensing propensity in specific organs of live organisms.
  • To investigate the role of electrophile responsiveness in tissue-specific stress responses and metabolite signaling.

Main Methods:

  • Development of a novel assay to measure electrophile responsivity in vivo.
  • Quantitative mapping and ranking of electrophile-responsive proteins across different tissues.
  • Characterization of the molecular mechanisms underlying Cyp-33e1's electrophile sensing and functional output.

Main Results:

  • >70% of tissue-specific responders demonstrated electrophile responsiveness, irrespective of protein abundance.
  • Identified Cyp-33e1 as an electrophile-responsive protein that regulates stress-dependent gut functions and lipid availability.
  • Demonstrated site-specific electrophile sensing by Cyp-33e1's cysteine residues, modulating gut homeostasis and metabolite signaling.

Conclusions:

  • Organ-specific electrophile responsivity mapping provides a powerful tool to uncover localized chemical interactions and signaling pathways.
  • This approach illuminates previously intractable locale-specific metabolite signaling and stress response programs.
  • Understanding organ-specific electrophile sensing is crucial for deciphering complex stress response mechanisms and organ-specific decision-making.