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Modular metabolite assembly in C. elegans lysosome-related organelles

Le, Henry H. and Wrobel, Chester J. and Cohen, Sarah M. and Yu, Jingfang and Park, Heenam and Helf, Maximilian J. and Curtis, Brian J. and Rodrigues, Pedro R. and Sternberg, Paul W. and Schroeder, Frank C. (2020) Modular metabolite assembly in C. elegans lysosome-related organelles. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200825-103646907

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Abstract

Signaling molecules derived from attachment of diverse primary 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 lysosome-related organelles (LROs) are required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Both modular glucosides and ascarosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism. We further show that cholinesterase (cest) homologs that localize to the LROs are required for assembly of both modular ascarosides and glucosides, mediating formation of ester and amide linkages between subsets of building blocks. Their specific biosynthesis suggests that modular glucosides, like ascarosides, serve dedicated signaling functions. Further exploration of LRO function and cest homologs in C. elegans and other animals may reveal additional new compound families and signaling paradigms.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.08.22.262956DOIDiscussion Paper
ORCID:
AuthorORCID
Le, Henry H.0000-0003-2942-2357
Wrobel, Chester J.0000-0001-6047-4644
Cohen, Sarah M.0000-0002-5233-2280
Yu, Jingfang0000-0003-1770-5368
Park, Heenam0000-0001-7911-5828
Helf, Maximilian J.0000-0002-1393-3999
Sternberg, Paul W.0000-0002-7699-0173
Schroeder, Frank C.0000-0002-4420-0237
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Posted August 24, 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. Author Contributions: The manuscript was written through contributions of all authors and all authors have given approval to the final version of the manuscript. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
NIH Predoctoral Fellowship5T32GM008500
NIHR35 GM131877
NIHR24OD023041
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Record Number:CaltechAUTHORS:20200825-103646907
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200825-103646907
Official Citation:Modular metabolite assembly in C. elegans lysosome-related organelles. Henry H Le, Chester J Wrobel, Sarah M Cohen, Jingfang Yu, Heenam Park, Maximilian J Helf, Brian J Curtis, Pedro R Rodrigues, Paul W Sternberg, Frank C Schroeder. bioRxiv 2020.08.22.262956; doi: https://doi.org/10.1101/2020.08.22.262956
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105100
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:25 Aug 2020 17:50
Last Modified:25 Aug 2020 17:50

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