Chemoproteomic identification of a DPP4 homolog in Bacteroides thetaiotaomicron
Open accessPublished version of a preprint
Abstract
Serine hydrolases have important roles in signaling and human metabolism, yet little is known about their functions in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Our functional studies reveal that BT4193 is a true homolog of hDPP4 that can be inhibited by FDA-approved type 2 diabetes medications targeting hDPP4, while the other is a misannotated proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and that loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. However, neither function is dependent on BT4193 proteolytic activity, suggesting a scaffolding or signaling function for this bacterial protease.
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Cites
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- Authors
- Keller, L. J., Nguyen, T. H., Liu, L. J., Hurysz, B. M., Lakemeyer, M., Guerra, M., Gelsinger, D. J., Chanin, R., Ngo, N., Lum, K. M., Faucher, F., Ipock, P., Niphakis, M. J., Bhatt, A. S., O’Donoghue, A. J., Huang, K. C., & Bogyo, M.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- University of California San Diego (US)
- Genentech (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Corresponding author
- Bogyo, Matthew
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2023-06-22
- Volume
- 19
- Issue
- 12
- Pages
- 1469-1479
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W4381612678
- Cited by
- 24
- References
- 4
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 8 · 2023: 2
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (DGE-165651 8, 1656518, 2125383)
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (DGE-1656518, AI147023, GM135102, HG000044)
- Chemistry, Engineering and Medicine for Human Health, Stanford University
- National Human Genome Research Institute (K22HG000044, T32HG000044)
- National Institute of General Medical Sciences (T32GM120007, T32GM007752, RM1GM135102, T32GM113854)
- National Institute of Allergy and Infectious Diseases (R01AI148623, R01AI147023, R01AI143757, R01AI158612)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK131005)
- National Institute of Biomedical Imaging and Bioengineering (R01EB026285, R01EB026332)
- Division of Graduate Education (1656518, DGE1656518)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
- Keywords
- Bacteroides thetaiotaomicron, serine hydrolases, chemoproteomics, gut commensal bacteria, Bacteroidetes, insulin signaling
- MeSH terms
- Bacteroides thetaiotaomicron, Diabetes Mellitus, Type 2, Humans, Serine, Dipeptidyl Peptidase 4
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