Abstract
The microbiota generates diverse metabolites to modulate host physiology and disease, but their protein targets and mechanisms of action have not been fully elucidated. To address this challenge, we explored microbiota-derived indole metabolites and developed photoaffinity chemical reporters for proteomic studies. We identified many potential indole metabolite-interacting proteins, including metabolic enzymes, transporters, immune sensors and G protein-coupled receptors. Notably, we discovered that aromatic monoamines can bind the orphan receptor GPRC5A and stimulate β-arrestin recruitment. Metabolomic and functional profiling also revealed specific amino acid decarboxylase-expressing microbiota species that produce aromatic monoamine agonists for GPRC5A-β-arrestin recruitment. Our analysis of synthetic aromatic monoamine derivatives identified 7-fluorotryptamine as a more potent agonist of GPRC5A. These results highlight the utility of chemoproteomics to identify microbiota metabolite-interacting proteins and the development of small-molecule agonists for orphan receptors.
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Data availability
The proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD040163. The metabolomics data have been searched in METLIN database and deposited to the XCMS Public with the dataset identifier 1529105. The RNA-seq data have been deposited to Gene Expression Omnibus with the accession number GSE225392. Human Microbiome Project Reference Genomes were downloaded via BioProject Accession number PRJNA28331. All other data supporting the findings of this study are available within the article and its Supplementary Information files, and from the corresponding author upon request. Source data are provided with this paper.
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Acknowledgements
We thank H. Molina from Proteomics Resource Center at Rockefeller University for proteomics and HRMS, G. Siuzdak and L.T. Hoang from the Scripps Center for Metabolomics and Mass Spectrometry for untargeted metabolomics, S.R. Head and J. Shimashita from Genomics Core at Scripps Research for RNA-seq, P. Natarajan and A. Sundaresan from Center for Computational Biology and Bioinformatics and W. Li at Scripps Research for RNA-seq data analysis. We also thank G. Barnea (Brown University) for providing HTLA cells, B. Roth (University of North Carolina) for PRESTO-Tango plasmids, S. Kitamura and F. Martinez (Scripps Research) for sharing aromatic monoamines, M. Gilmore (Harvard Medical School) for E. faecium Com15, S. F. Brady (The Rockefeller University) for R. gnavus ATCC 29149, and C.-J. Guo (Weill Cornell Medical School) for C. sporogenes ATCC 15579. K.S. acknowledges support from Scripps Research Department of Immunology and Microbiology T32AI007244 grant. L.L.L acknowledges grant support from NIH-NINDS R01NS112482-02. H.C.H. acknowledges grant support from NIH-NIGMS R01GM087544.
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X.Z. and H.C.H. conceived the project. K.R.S. contributed to the generation of GPRC5A-KO cell lines and flow cytometry analysis of GPRC5A mutants, V.C. prepared TyrDC-KO E. faecium Com15, M.E.G. performed phylogenetic analysis of bacterial decarboxylases and L.L.L. provided the aromatic monoamine derivatives. X.Z. performed the experiments and interpreted the data. X.Z. and H.C.H. wrote the manuscript with input from K.R.S., V.C., M.E.G. and L.L.L.
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Extended data
Extended Data Fig. 1 Chemoproteomic analysis of indole-3-acetic acid-interacting proteins.
a, Scheme for in-gel fluorescence profiling and chemoproteomic analysis of microbiota metabolite protein targets in HT-29 cells using photoaffinity chemical reporters. b, In-gel fluorescence profiling of IAA-interacting proteins in HT-29 cells using indicated concentration of x-alk-IAA with or without UV irradiation. At least two independent experiments were performed. c, Volcano plot of the identified proteins from HT-29 cells by chemical proteomics using x-alk-IAA with UV irradiation compared to DMSO control (p value is 0.05, two folds change in four replicates from two sample t-test). Some of key hits are highlighted in GPCRs (green), transporters (blue) and immunity-associated proteins (red). d, Venn diagram for the statistically significant hits identified by chemical proteomics using two chemical reporters with or without UV irradiation. e, Gene ontology analysis of the major subcellular localization, Fisher’s exact test. f, KEGG pathway analysis of the statistically significant proteins identified in HT-29 cells using x-alk-IAA with UV irradiation from the hypergeometric test.
Extended Data Fig. 2 Chemoproteomic analysis of tryptamine-interacting proteins.
a, PRESTO-Tango assay for screening a collection of indole derivatives (100 µM) on ADRA2A, GPRC5A, GPR107 and GPR108. 0.1% DMSO were used as controls. b-c, ADRA2A and GPRC5A are crosslinked by IAA photoaffinity chemical reporters. Competitive labeling assay using 200 µM IAA or TA that compete with 20 µM x-alk-IAA in binding on ADRA2A or GPRC5A. d, In-gel fluorescence profiling of IAA- or TA-interacting proteins in A549 cells using indicated concentration of x-alk-IAA or x-alk-TA with or without UV irradiation. At least two independent experiments were performed. e, Volcano plot of the identified proteins from A549 cells by chemical proteomics using x-alk-IAA or x-alk-TA with UV irradiation (p value is 0.05, two folds change in four replicates). f, Pull-down of endogenous GPRC5A from A549 cells that were photo-crosslinked by x-alk-IAA or x-alk-TA followed by biotin labeling and neutravidin enrichment. At least two independent experiments were performed. Data indicates mean with SEM from three replicates (a,c). Two-way ANOVA using Holm-Sidak’s multiple comparisons test (a, c), ****P < 0.0001.
Extended Data Fig. 3 Targeted metabolomics of microbiota species.
a, LC-MS analysis of the concentration of aromatic monoamines in different bacterial cultures. Data indicates individual value of three replicates. b, Western blot analysis of the overexpression of His6-tagged E. faecium Com15 tyrosine decarboxylase (Efm_TyrDC), R. gnavus tryptophan decarboxylase (Rgs_TrpDC) or M. morganii glutamate/tyrosine decarboxylase (Mmi_Gln/TyrDC) in E. coli DH5α. c, Bacterial growth in minimal media supplemented with individual aAAs at 37 °C for 16 h. Data indicates mean with SEM from three replicates. d. LC-MS analysis of aromatic monoamines produced by overexpression of Efm_TyrDC, Rgs_TrpDC or Mmi_Gln/TyrDC in E. coli DH5α. Data indicates individual value of three replicates.
Extended Data Fig. 4 Enzyme kinetics of E. faecium Com15 tyrosine decarboxylase.
a, SDS-PAGE analysis of the purification of His6-tagged E. faecium Com15 tyrosine decarboxylase (Efm_TyrDC). At least two independent experiments were performed. b, LC-MS analysis of the time-dependent formation of tyramine from enzymatic transformation of tyrosine by 100 nM Efm_TyrDC at room temperature. c, LC-MS determination of tryptamine, tyramine, phenethylamine and histamine from enzymatic transformation of tryptamine, tyrosine, phenylalanine and histidine by 100 nM Efm_TyrDC at 37 °C for 10 min. d, PRESTO-Tango assay for Efm_TyrDC enzymatic products for GPRC5A activation. e, Michaeslis-Menten kinetics study of Efm_TyrDC catalyzed transformation of tyrosine and phenylalanine. Data indicates mean with SEM from three replicates (d). Two-way ANOVA using Sidak’s multiple comparisons test, ****p < 0.0001.
Extended Data Fig. 5 Genetic manipulation of E. faecium Com15 TyrDC.
a, Genetic deletion of segment of DNA disrupts TyrDC gene expression in E. faecium Com15. b, Agarose gel electrophoresis of the PCR products from wild-type and TyrDC gene-disrupted E. faecium Com15. c, Optical density measurement of bacterial growth including wild-type E. faecium Com15 (Efm_wt), E. faecium Com15 TyrDC knock-out (Efm_Δtdc), complementation of vector control (pKH12) or TyrDC (pKH12-tdc) in Efm_Δtdc at 37 °C for 16 h. d, PRESTO-Tango assay for examining bacterial cultures for GPRC5A activation. Bacterial growth media were filtered through 0.2 µM membrane followed by 3,000 MWKO membrane. Data indicates mean with SEM from three replicates (c,d).
Extended Data Fig. 6 Untargeted metabolomics of E. faecium Com15.
a, Principal component analysis (PCA) of the molecular features identified by the untargeted metabolomics of BHI media, E. faecium Com15 wild-type (Efm_WT) and tyrDC deletion strain (Efm_∆tdc) cultures. b, Volcano plot of the molecular features from Efm_WT and Efm_∆tdc strains. Dashed lines indicate q-value = 0.01, five folds change in five replicates. c, Fold change ranking of representative metabolites identified in Efm_WT in comparison with Efm_∆tdc cultures. d-g, Mass intensity of the representative metabolites identified in Efm_WT cultures. Data indicates mean with SEM from five replicates. h, PRESTO-Tango assay for the representative aromatic amines. Data indicates mean with SEM from three replicates.
Extended Data Fig. 7 Screening of aromatic monoamine derivatives.
a, PRESTO-Tango assay for screening a collection of tryptamine derivatives (100 µM) for GPRC5A activation. b, Dose-response curves of GPRC5A activation upon aromatic monoamines treatment. c, d, LDH cytotoxicity assay and MTT cell viability assay in mammalian cells. e, PRESTO-Tango assay for screening a collection of aromatic monoamines and phenylethylamine derivatives (100 µM) for GPRC5A activation. Data indicates mean with SEM from three replicates (a,b,c,d). One-way ANOVA using Dunnett’s multiple comparisons test.
Extended Data Fig. 8 PRESTO-Tango assay for GPCRs.
a, b, Evaluation of 100 µM of TA and 7FTA on class C orphan GPCRs (GPRC5A,B,C,D) and aminergic GPCRs (ADRA2A, DRD2, HTR4) activation. c, Dose-response curves of 7FTA on class C orphan GPCRs (GPRC5A,B,C,D) and aminergic GPCRs (ADRA2A, DRD2, HTR4) activation. d, Examination of endogenous neurotransmitters epinephrine (10 µM), dopamine (10 µM) and serotonin (100 µM) on GPRC5A activation e, Western blot analysis of FLAG-tagged GPCR-Tango constructs in HTLA cells. At least two independent experiments were performed. Data indicates mean with SEM from three replicates (a,b,c,d). Two-way ANOVA using Tukey’s multiple comparisons test (a-b), One-way ANOVA using Dunnett’s multiple comparisons test (b), ****p < 0.0001.
Extended Data Fig. 9 Assays for GPRC5A signaling.
a, NF-κB-dependent luciferase reporter assay in HEK293 cells transfected with different amount of vector, GRPC5A or ADRA2A plasmids followed by the treatment 10 ng/mL TNFα for 8 h. b, Dose response curves of 7FTA in the NF-κB-dependent luciferase reporter assay. HEK293 cells transfected with vector or GRPC5A plasmids were treated with increasing concentration of 7FTA with or without 10 ng/mL TNFα for 8 h. 0.1% DMSO was used as the vehicle control. c, Dose response curves of 7FTA in the G-protein activated luciferase reporter assay. HEK293 cells were transfected with GPRC5A plasmid and reporter plasmids for cAMP response element (CRE), nuclear factor of activated T-Cells (NFAT), or serum response element (SRE). Cells were then treated with increasing concentrations of 7FTA for 8 h. In CRE + forskolin samples, cells were also treated with 1 µM forskolin. d, BRET-based TRUPATH assay for GPRC5A in HEK293 cells upon DMSO or 100 µM 7FTA treatment. Data indicates mean with SEM from three replicates (a,b,c,d). Two-way ANOVA using Tukey’s multiple comparisons test (a-b), ****p < 0.0001.
Extended Data Fig. 10 RNAseq analysis of wild-type and GPRC5A-KO HT-29 cells.
a, Principal component analysis (PCA) plot of RNAseq data for wild-type and GPRC5A-KO HT-29 cells upon treatment with 0.1% DMSO, 50 µM 7FTA, 10 ng/mL TNFa with or without 7FTA. b, Volcano plot for the differential gene expression in wild-type HT-29 cells upon treatment with 0.1% DMSO or 50 µM 7FTA. Significant genes indicate an adjusted p value <0.05 and two folds change in three replicates. c, RT-qPCR analysis of respective fold gene expression level against ACTB for wild-type and GPRC5A-KO cells treatment with DMSO or 7FTA. Data represent fold gene expression in four replicates. d–f, RT-qPCR analysis of respective fold gene expression level for wild-type and GPRC5A-KO cells treated 0.1% DMSO, 10 ng/mL TNFα with or without 50 µM 7FTA for 8 h. Data indicates mean with SEM from four replicates (d,e) and three replicates (f). One-way ANOVA using Tukey’s multiple comparisons test, ****p < 0.0001.
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Zhao, X., Stein, K.R., Chen, V. et al. Chemoproteomics reveals microbiota-derived aromatic monoamine agonists for GPRC5A. Nat Chem Biol 19, 1205–1214 (2023). https://doi.org/10.1038/s41589-023-01328-z
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DOI: https://doi.org/10.1038/s41589-023-01328-z
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