Organ-specific electrophile responsivity mapping in live C. elegans
Year: 2024
Type: preprint
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-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 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 BRIEF Context-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. HIGHLIGHTS Localis-REX maps organ-specific electrophile-responsive proteins in worms Hits are neither identified by organ-specific Ultra-ID nor biased by localized expression Hits are enriched in proteins functionally relevant to stress-related phenotypes Localized responsivity of gut-specific hit, cyp-33e1, shapes global lipid availability
Authors: Jinmin Liu, Amogh Kulkarni, Yong-Qi Gao, Daniel A. Urul, Romain Hamelin, Balázs Á. Novotny, Marcus J. C. Long, Yimon Aye
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4402939440