PGLYRP1-mediated intracellular peptidoglycan detection promotes intestinal mucosal protection

Shuyuan Chen, Rachel Putnik, Xi Li, Alka Diwaker, Marina Vasconcelos, Shuzhen Liu, Sudershan Gondi, Junhui Zhou, Lei Guo, Lin Xu, Sebastian Temme, Klare Bersch, Stephen Hyland, Jianyi Yin, Ezra Burstein, Brian J. Bahnson, Jeffrey C. Gildersleeve, Catherine Leimkuhler Grimes () and Hans-Christian Reinecker ()
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Shuyuan Chen: University of Texas Southwestern Medical Center
Rachel Putnik: University of Delaware
Xi Li: University of Texas Southwestern Medical Center
Alka Diwaker: University of Texas Southwestern Medical Center
Marina Vasconcelos: University of Delaware
Shuzhen Liu: University of Texas Southwestern Medical Center
Sudershan Gondi: University of Texas Southwestern Medical Center
Junhui Zhou: University of Delaware
Lei Guo: University of Texas Southwestern Medical Center
Lin Xu: University of Texas Southwestern Medical Center
Sebastian Temme: National Cancer Institute
Klare Bersch: University of Delaware
Stephen Hyland: University of Delaware
Jianyi Yin: University of Texas Southwestern Medical Center
Ezra Burstein: University of Texas Southwestern Medical Center
Brian J. Bahnson: University of Delaware
Jeffrey C. Gildersleeve: National Cancer Institute
Catherine Leimkuhler Grimes: University of Delaware
Hans-Christian Reinecker: University of Texas Southwestern Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57126-9

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