Organ-specific electrophile responsivity mapping in live C. elegans

Proximity labeling technologies are limited to indexing localized protein residents. Such data-although valuable-cannot inform on small-molecule responsivity of local residents. We here bridge this gap by demonstrating in live C. elegans how electrophile-sensing propensity in specific organs can be...

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Bibliographic Details
Published in:Cell Vol. 187; no. 26; p. 7450
Main Authors: Liu, Jinmin, Kulkarni, Amogh, Gao, Yong-Qi, Urul, Daniel A, Hamelin, Romain, Novotny, Balázs Á, Long, Marcus J C, Aye, Yimon
Format: Journal Article
Language:English
Published: United States 26.12.2024
Subjects:
Animals
Caenorhabditis elegans - metabolism
Caenorhabditis elegans Proteins - metabolism
Cysteine - metabolism
Cytochrome P-450 Enzyme System - metabolism
Humans
Organ Specificity
Stress, Physiological
reactive metabolite signaling
tissue-specific stress response
proximity labeling proteomics
C. elegans
organ-specific responsivity profiling
cytochrome P450
4-hydroxynonenal
function-guided spatial mapping
ISSN:1097-4172, 1097-4172
Online Access:Get more information
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Summary:Proximity labeling technologies are limited to indexing localized protein residents. Such data-although valuable-cannot inform on small-molecule responsivity of local residents. We here bridge this gap by demonstrating in live C. elegans how electrophile-sensing propensity in specific organs can be quantitatively mapped and ranked. Using this method, >70% of tissue-specific responders exhibit electrophile responsivity, independent of tissue-specific abundance. One responder, cyp-33e1-for which both human and worm orthologs are electrophile responsive-marshals stress-dependent gut functions, despite manifesting uniform abundance across all tissues studied. Cyp-33e1's localized electrophile responsivity operates site specifically, triggering multifaceted responses: electrophile sensing through the catalytic-site cysteine results in partitioning between enzyme inhibition and localized production of a critical metabolite that governs global lipid availability, whereas rapid dual-cysteine site-specific sensing modulates gut homeostasis. Beyond pinpointing chemical actionability within local proteomes, organ-specific electrophile responsivity mapping illuminates otherwise intractable locale-specific metabolite signaling and stress response programs influencing organ-specific decision-making.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2024.10.014