Chen Shuyuan, Putnik Rachel, Li Xi, Diwaker Alka, Vasconcelos Marina, Liu Shuzhen, Zhou Junhui, Guo Lei, Xu Lin, Temme Sebastian, Bersch Klare, Hyland Stephen, Yin Jianyi, Burstein Ezra, Gildersleeve Jeffrey C, Grimes Catherine Leimkuhler, Reinecker Hans-Christian
Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, Texas 75390, United States.
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States National Cancer Institute.
Res Sq. 2024 Oct 14:rs.3.rs-5118704. doi: 10.21203/rs.3.rs-5118704/v1.
Peptidoglycan recognition proteins (PGRPs or PGLYRPs) are implicated in the control of the intestinal microbiota; however, molecular requirements for peptidoglycan (PGN) binding and receptor signaling mechanisms remain poorly understood. We identified PGLYRP-1 as a receptor for the disaccharide motif of lysine N-acetylglucosamine N-acetylmuramic tripeptide (GMTriP-K) with a newly constructed PGN microarray. Surprisingly, PGLYRP-1 was required for innate immune activation of macrophages by GMTriP-K but not N-acetylglucosamine N-acetylmuramic dipeptide (GMDiP) or muramyl dipeptide (MDP). In macrophages, intracellular PGLYRP-1 complexed with NOD2 and GEF-H1, both of which were required for GMTriP-K-regulated gene expression. PGLYRP-1 localized to the endoplasmic reticulum and interacted at the Golgi with NOD2 upon GMTriP-K stimulation. PGLYRP-1 upregulation and its dependent gene expression signatures were induced in both mouse intestinal inflammation and human ulcerative colitis. Importantly, PGLYRP-1 activation by GMTriP-K resulted in innate immune activation and protection of mice from colitis. Our results show that PGLYRPs can function as intracellular PGN pattern recognition receptors for the control of host defense responses in the intestine.
肽聚糖识别蛋白（PGRPs 或 PGLYRPs）与肠道微生物群的控制有关；然而，对于肽聚糖（PGN）结合的分子要求和受体信号传导机制仍知之甚少。我们通过新构建的 PGN 微阵列鉴定出 PGLYRP-1 是赖氨酸 N-乙酰葡糖胺 N-乙酰胞壁酸三肽（GMTriP-K）二糖基序的受体。令人惊讶的是，GMTriP-K 激活巨噬细胞的天然免疫需要 PGLYRP-1，但 N-乙酰葡糖胺 N-乙酰胞壁酸二肽（GMDiP）或胞壁酰二肽（MDP）则不需要。在巨噬细胞中，细胞内的 PGLYRP-1 与 NOD2 和 GEF-H1 结合，这两者都是 GMTriP-K 调节基因表达所必需的。在 GMTriP-K 刺激下，PGLYRP-1 定位于内质网并在高尔基体与 NOD2 相互作用。在小鼠肠道炎症和人类溃疡性结肠炎中均诱导了 PGLYRP-1 的上调及其依赖的基因表达特征。重要的是，GMTriP-K 激活 PGLYRP-1 可导致天然免疫激活并保护小鼠免受结肠炎的侵害。我们的结果表明，PGLYRPs 可作为细胞内 PGN 模式识别受体，用于控制肠道中的宿主防御反应。
