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Molybdenum cofactor transfer from bacteria to nematode mediates sulfite detoxification

Abstract

The kingdoms of life share many small molecule cofactors and coenzymes. Molybdenum cofactor (Moco) is synthesized by many archaea, bacteria, and eukaryotes, and is essential for human development. The genome of Caenorhabditis elegans contains all of the Moco biosynthesis genes, and surprisingly these genes are not essential if the animals are fed a bacterial diet that synthesizes Moco. C. elegans lacking both endogenous Moco synthesis and dietary Moco from bacteria arrest development, demonstrating interkingdom Moco transfer. Our screen of Escherichia coli mutants identifies genes necessary for synthesis of bacterial Moco or transfer to C. elegans. Developmental arrest of Moco-deficient C. elegans is caused by loss of sulfite oxidase, a Moco-requiring enzyme, and is suppressed by mutations in either C. elegans cystathionine gamma-lyase or cysteine dioxygenase, blocking toxic sulfite production from cystathionine. Thus, we define the genetic pathways for an interkingdom dialogue focused on sulfur homeostasis.

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Fig. 1: Moco acquisition and biosynthesis are redundantly required for life in C. elegans.
Fig. 2: C. elegans acquire cPMP and Moco from dietary E. coli.
Fig. 3: cth-2 and cdo-1 are necessary for the growth arrest and death caused by Moco deficiency.
Fig. 4: Endogenously produced sulfites inhibit growth and development during Moco deficiency.
Fig. 5: suox-1 hypomorphic allele phenocopies Moco deficiency in C. elegans.
Fig. 6: Tissue-specific rescue of moc-1 and cth-2.

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Acknowledgements

We thank the Caenorhabditis Genetics Center, M. Han, V. Ambros, and S. Mitani for providing C. elegans strains. We thank M.-A. Félix for providing wild bacterial isolates and the National BioResource Project (NIG, Japan) for providing the Keio E. coli knockout collection. This work was funded by an NIH Grant (5R01GM044619-26) to G.R. and a Damon Runyon Fellowship (DRG-2293-16) to K.W.

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K.W. and G.R. designed experiments, and K.W. performed experiments. K.W. and G.R. wrote the manuscript.

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Correspondence to Gary Ruvkun.

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Supplementary Tables 1–5, Supplementary Figures 1–7

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Warnhoff, K., Ruvkun, G. Molybdenum cofactor transfer from bacteria to nematode mediates sulfite detoxification. Nat Chem Biol 15, 480–488 (2019). https://doi.org/10.1038/s41589-019-0249-y

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