PGLYRP-1 mediated intracellular peptidoglycan detection promotes mucosal protection

PGLYRP-1 mediated intracellular peptidoglycan detection promotes mucosal protection | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article PGLYRP-1 mediated intracellular peptidoglycan detection promotes mucosal protection Hans-Christian Reinecker, Shuyuan Chen, Rachel Putnik, Xi Li, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5118704/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Feb, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract 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. Biological sciences/Immunology/Mucosal immunology Biological sciences/Immunology/Gene regulation in immune cells Biological sciences/Immunology/Innate immunity/Pattern recognition receptors/NOD-like receptors Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TableS1.xlsx Table S1 TABS2.xlsx Table S2 TABS3.xlsx Table S3 TabS4.xlsx Table S4 TabS5.xlsx Table S5 TableS6.xlsx Table S6 TableS7.xlsx Table S7 TableS8.xlsx Table S8 TableS9.xlsx Table S9 TableS10.xlsx Table S10 TabS11.xlsx Table S11 TabS12.xlsx Table S12 TabS13.xlsx Table S13 TabS14.xlsx Table S14 TabS15.docx Table S15 SupplementaryInformationReinecker.pdf PGLYRP-1 mediated intracellular peptidoglycan detection promotes mucosal protection Cite Share Download PDF Status: Published Journal Publication published 21 Feb, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5118704","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":357243690,"identity":"5805cdda-7585-46cd-97b5-7bcf42a8c776","order_by":0,"name":"Hans-Christian Reinecker","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-8283-644X","institution":"University of Texas Southwestern Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Hans-Christian","middleName":"","lastName":"Reinecker","suffix":""},{"id":357243691,"identity":"0553b286-d8a2-4fa0-88cf-529a2419a197","order_by":1,"name":"Shuyuan Chen","email":"","orcid":"","institution":"University of Texas Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Shuyuan","middleName":"","lastName":"Chen","suffix":""},{"id":357243692,"identity":"d6c482c2-ac47-469b-8c1a-4104bc6a8694","order_by":2,"name":"Rachel Putnik","email":"","orcid":"","institution":"University of Delaware","correspondingAuthor":false,"prefix":"","firstName":"Rachel","middleName":"","lastName":"Putnik","suffix":""},{"id":357243693,"identity":"9901ea2e-ea5c-4490-8663-cf3986678a67","order_by":3,"name":"Xi Li","email":"","orcid":"","institution":"University of Texas Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Li","suffix":""},{"id":357243694,"identity":"152e2a39-97af-49c7-b455-aeeeb1d2abd7","order_by":4,"name":"Alka Diwaker","email":"","orcid":"","institution":"University of Texas Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Alka","middleName":"","lastName":"Diwaker","suffix":""},{"id":357243695,"identity":"95fece40-769c-49a4-bffe-98e97cac77ac","order_by":5,"name":"Marina Vasconcelos","email":"","orcid":"https://orcid.org/0009-0000-9178-9841","institution":"University of Delaware","correspondingAuthor":false,"prefix":"","firstName":"Marina","middleName":"","lastName":"Vasconcelos","suffix":""},{"id":357243696,"identity":"1f23bb39-8214-4fde-bf6b-3ed1c5f307b6","order_by":6,"name":"Shuzhen Liu","email":"","orcid":"","institution":"University of Texas Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Shuzhen","middleName":"","lastName":"Liu","suffix":""},{"id":357243697,"identity":"586eb3df-7278-4208-a0cf-f7bcb25e11ad","order_by":7,"name":"Junhui Zhou","email":"","orcid":"","institution":"University of Delaware","correspondingAuthor":false,"prefix":"","firstName":"Junhui","middleName":"","lastName":"Zhou","suffix":""},{"id":357243698,"identity":"e0f356a5-7190-48e4-b921-afa5b1686283","order_by":8,"name":"Lei Guo","email":"","orcid":"","institution":"UT Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Guo","suffix":""},{"id":357243699,"identity":"0c30fa82-2a2d-42f9-9d4f-505991d6e7ad","order_by":9,"name":"Lin Xu","email":"","orcid":"https://orcid.org/0000-0001-5815-4457","institution":"University of Texas Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Xu","suffix":""},{"id":357243700,"identity":"84c08221-df82-43bc-bd4b-dd4cc573bf09","order_by":10,"name":"J. 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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. 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