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bioRxiv · 10.1101/2024.09.27.615266

Organ-specific electrophile responsivity mappingin live C. elegans

Liu, J.·Kulkarni, A.·Gao, Y.-Q.·Urul, D. A.·Hamelin, R.·Novotny, B. A.·Long, M. J. C.·Aye, Y.
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Abstract

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 novel 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-33e1s 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 a rapid dual-cysteine site-specific sensing modulates gut homeostasis. Beyond pinpointing chemical actionability within local proteomes, tissue-specific electrophile responsivity mapping illuminates otherwise intractable locale-specific metabolite signaling and stress response programs influencing organ-specific decision-making. IN BRIEFContext-specific protein reactivity is a cornerstone of biological stress responsivity, and thus has important ramifications for drug discovery; no current method can inform on these parameters. Here we debut a method that cartographs locale-specific actionability to reactive metabolites; Cyp-33e1, a gut-specific responder, emerged to partition between electrophile-driven localized enzymatic turnover that triggers gut-specific metabolite production shaping global lipid storage, and localized electrophile sensing that marshals global stress response. HIGHLIGHTSO_LILocalis-REX maps organ-specific electrophile-responsive proteins in worms C_LIO_LIHits are neither identified by organ-specific Ultra-ID nor biased by localized expression C_LIO_LIHits are enriched in proteins functionally relevant to stress-related phenotypes C_LIO_LILocalized responsivity of gut-specific hit, cyp-33e1, shapes global lipid availability C_LI

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Liu, J., Kulkarni, A., Gao, Y.-Q., Urul, D. A., Hamelin, R., Novotny, B. A., Long, M. J. C., Aye, Y.. 2024-09-28. Organ-specific electrophile responsivity mappingin live C. elegans. https://doi.org/10.1101/2024.09.27.615266

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