PGLYRP1-mediated intracellular peptidoglycan detection promotes intestinal mucosal protection
Peptidoglycan recognition proteins (PGLYRPs) are implicated in the control of the intestinal microbiota; however, molecular requirements for peptidoglycan (PGN) binding and receptor signaling mechanisms remain poorly understood. Here we show that PGLYRP1 is a receptor for the disaccharide motif of lysine N-acetylglucosamine N-acetylmuramic tripeptide (GMTriP-K). PGLYRP1 is required for innate immune activation by GMTriP-K but not muramyl dipeptide (MDP). In macrophages, intracellular PGLYRP1 complexes with NOD2 and GEF-H1, both of which are required for GMTriP-K-regulated gene expression. PGLYRP1 localizes to the endoplasmic reticulum and interacts at the Golgi with NOD2 upon GMTriP-K stimulation. PGLYRP1 and dependent gene expression signatures are induced in both mouse intestinal inflammation and human ulcerative colitis. Importantly, PGLYRP1 activation by GMTriP-K can result in the protection of mice from TNBS-induced colitis. Mammalian PGLYRPs can function as intracellular pattern recognition receptors for the control of host defense responses in the intestine.
Authors
- Rachel Putnik (ORCID: https://orcid.org/0000-0002-3572-3677)
- Lei Guo (ORCID: https://orcid.org/0000-0002-7365-0405)
- Junhui Zhou (ORCID: https://orcid.org/0000-0002-1292-3801)
- Jeffrey C. Gildersleeve (ORCID: https://orcid.org/0000-0002-3744-6423)
- Ezra Burstein (ORCID: https://orcid.org/0000-0003-4341-6367)
- Sudershan Reddy Gondi (ORCID: https://orcid.org/0000-0002-1363-2352)
- Stephen N. Hyland (ORCID: https://orcid.org/0000-0002-3268-8140)
- Jianyi Yin (ORCID: https://orcid.org/0000-0002-1305-5399)
- Marina Vasconcelos
- Catherine L. Grimes (ORCID: https://orcid.org/0000-0002-0586-2879)
- J. Sebastian Temme (ORCID: https://orcid.org/0000-0001-8306-2810)
- Lin Xu (ORCID: https://orcid.org/0000-0001-5815-4457)
- Hans-Christian Reinecker (ORCID: https://orcid.org/0000-0001-8283-644X)
- Brian J. Bahnson (ORCID: https://orcid.org/0000-0002-1562-8314)
- Klare L. Bersch
- Shuzhen Liu (ORCID: https://orcid.org/0000-0002-0602-3217)
- Shuyuan Chen (ORCID: https://orcid.org/0009-0002-7751-9073)
- Zhiheng Li (ORCID: https://orcid.org/0000-0002-2977-2624)
- Alka Diwaker (ORCID: https://orcid.org/0009-0002-2473-6074)
Institutions
- Southwestern Medical Center (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- University of Delaware (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1038/s41467-025-57126-9
- Citations
- 15
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 12.09
Funders
- National Institutes of Health
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases