Chemoproteomic identification of a DPP4 homolog in Bacteroides thetaiotaomicron

Laura J Keller; Taylor H Nguyen; Lawrence J Liu; Brianna M Hurysz; Markus Lakemeyer; Matteo Guerra; Danielle J Gelsinger; Rachael Chanin; Nhi Ngo; Kenneth M Lum; Franco Faucher; Phillip Ipock; Micah J Niphakis; Ami S Bhatt; Anthony J O'Donoghue; Kerwyn Casey Huang; Matthew Bogyo

doi:10.1038/s41589-023-01357-8

Chemoproteomic identification of a DPP4 homolog in Bacteroides thetaiotaomicron

Nat Chem Biol. 2023 Dec;19(12):1469-1479. doi: 10.1038/s41589-023-01357-8. Epub 2023 Jun 22.

Authors

Laura J Keller¹, Taylor H Nguyen², Lawrence J Liu³, Brianna M Hurysz³, Markus Lakemeyer^{4

5}, Matteo Guerra^{4

6}, Danielle J Gelsinger³, Rachael Chanin^{7

8}, Nhi Ngo⁹, Kenneth M Lum⁹, Franco Faucher¹⁰, Phillip Ipock⁴, Micah J Niphakis⁹, Ami S Bhatt^{7

8}, Anthony J O'Donoghue³, Kerwyn Casey Huang^{2

11

12}, Matthew Bogyo^{13

14}

Affiliations

¹ Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Bioengineering, Stanford University, Stanford, CA, USA.
³ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
⁴ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich-Schiller-University, Jena, Germany.
⁶ Department of Biochemical and Cellular Pharmacology, Genentech, San Francisco, CA, USA.
⁷ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Divisions of Hematology and Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, CA, USA.
⁹ Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.
¹⁰ Department of Chemistry, Stanford University, Stanford, CA, USA.
¹¹ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
¹² Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹³ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹⁴ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].

PMID: 37349583
DOI: 10.1038/s41589-023-01357-8

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.

MeSH terms

Bacteroides thetaiotaomicron*
Diabetes Mellitus, Type 2*
Dipeptidyl Peptidase 4 / genetics
Humans
Serine

Substances

Dipeptidyl Peptidase 4
Serine

Grants and funding

RM1 GM135102/GM/NIGMS NIH HHS/United States