Modular metabolite assembly in Caenorhabditis elegans depends on carboxylesterases and formation of lysosome-related organelles
Abstract
Signaling molecules derived from attachment of diverse metabolic building blocks to ascarosides play a central role in the life history of C. elegans and other nematodes; however, many aspects of their biogenesis remain unclear. Using comparative metabolomics, we show that a pathway mediating formation of intestinal lysosome-related organelles (LROs) is required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Similar to modular ascarosides, the modular glucosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism, suggesting that modular glucosides, like the ascarosides, may serve signaling functions. We further show that carboxylesterases that localize to intestinal organelles are required for the assembly of both modular ascarosides and glucosides via ester and amide linkages. Further exploration of LRO function and carboxylesterase homologs in C. elegans and other animals may reveal additional new compound families and signaling paradigms.
Additional Information
© 2020 Le et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 07 August 2020; Accepted: 14 October 2020; Published: 16 October 2020. This research was funded by an NIH Chemical Biology Interface (CBI) Training Grant 5T32GM008500 (to B.C.), National Institutes of Health grants R35 GM131877 (to F.C.S.), and R24OD023041 (to P.W. S.). F.C.S. is a Faculty Scholar of the Howard Hughes Medical Institute. We thank WormBase for sequences, Tsui-Fen Chou for Cas9 protein, Ying (Kitty) Zhang for assistance with NMR spectroscopy, and Navid Movahed for assistance with mass spectrometry. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Author contributions: Henry H Le, Chester JJ Wrobel, Conceptualization, Data curation, Formal analysis, Investigation, Writing - original draft, Writing - review and editing; Sarah M Cohen, Conceptualization, Resources, Methodology; Jingfang Yu, Resources, Formal analysis; Heenam Park, Resources, Methodology; Maximilian J Helf, Software, Methodology; Brian J Curtis, Resources, Investigation; Joseph C Kruempel, Patrick J Hu, Resources; Pedro Reis Rodrigues, Data curation, Investigation; Paul W Sternberg, Conceptualization, Funding acquisition, Writing - original draft, Project administration, Writing - review and editing; Frank C Schroeder, Conceptualization, Formal analysis, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review and editing. Data availability: All data generated or analysed during this study are included in the manuscript and supporting files. MS/MS data is available via MassIVE under accession number: MSV000086293.Attached Files
Published - elife-61886-v2.pdf
Accepted Version - elife-61886-v1.pdf
Submitted - 2020.08.22.262956v2.full.pdf
Supplemental Material - elife-61886-supp-v1.zip
Supplemental Material - elife-61886-supp1-v2.pdf
Supplemental Material - elife-61886-transrepform-v2.docx
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Additional details
- Alternative title
- Modular metabolite assembly in C. elegans depends on carboxylesterases and formation of lysosome-related organelles
- PMCID
- PMC7641594
- Eprint ID
- 106016
- Resolver ID
- CaltechAUTHORS:20201013-104022895
- NIH Predoctoral Fellowship
- 5T32GM008500
- NIH
- R35 GM131877
- NIH
- R24OD023041
- Howard Hughes Medical Institute (HHMI)
- Created
-
2020-10-13Created from EPrint's datestamp field
- Updated
-
2023-06-02Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering (BBE)