The C-type lectin receptor DCIR senses galactose-terminated N-glycans on LRP1 to regulate myeloid cell function

The C-type lectin receptor DCIR senses galactose-terminated N-glycans on LRP1 to regulate myeloid cell function | 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 Article The C-type lectin receptor DCIR senses galactose-terminated N-glycans on LRP1 to regulate myeloid cell function Yoann Rombouts, Benjamin Raymond, Tamara Sneperger, Stella Rousset, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7879894/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor expressed in myeloid cells. Although patient and experimental data implicates DCIR in diverse diseases, including chronic inflammation, autoimmunity, allergy, infection, and cancer, the physiological ligand of DCIR remains elusive, leaving both its precise role in immunoregulation and its potential for therapeutic targeting unclear. Here, we identify the low-density lipoprotein receptor-related protein 1 (LRP1), a ubiquitously expressed, highly glycosylated membrane receptor, as a conserved endogenous ligand for human DCIR and murine DCIR1. DCIR specifically interacts with LRP1 through galactose-terminated biantennary complex-type N-glycans. By combining X-ray crystallography, small angle X-ray scattering, and site-directed mutagenesis, we define the structural organization of DCIR as a dimeric receptor and the basis of DCIR-glycan recognition, revealing key contact residues and an atypical glycan-binding mode. We further demonstrate that DCIR is activated through cis-interactions with its ligand upon co-engagement of ITAM-containing receptors, such as Dectin-1 or FcγRs, and modulates FcγR-mediated phagocytosis. Overall, our study addresses a long-standing gap by identifying the physiological ligand of DCIR, uncovering a novel glyco-immune recognition axis, and opening avenues for targeted intervention in DCIR-associated diseases. Biological sciences/Biochemistry/Structural biology/X-ray crystallography Biological sciences/Biochemistry/Structural biology/SAXS Biological sciences/Immunology Biological sciences/Biochemistry/Glycobiology Biological sciences/Biochemistry/Proteomics Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TableS3.xlsx Table S3 TableS2.xlsx Table S2 TableS4.xlsx Table S4 TableS6.xlsx Table S6 TableS1.xlsx Table S1 TableS5.xlsx Table S5 TableS7.xlsx Table S7 RaymondSnepergerRousset2025SupplementalNSMBFinal.pdf Supplementary informations and figures Cite Share Download PDF Status: Under Review 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7879894","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":535671088,"identity":"ab33414c-36a9-4a10-9f1d-67461a050b11","order_by":0,"name":"Yoann 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Although patient and experimental data implicates DCIR in diverse diseases, including chronic inflammation, autoimmunity, allergy, infection, and cancer, the physiological ligand of DCIR remains elusive, leaving both its precise role in immunoregulation and its potential for therapeutic targeting unclear. Here, we identify the low-density lipoprotein receptor-related protein 1 (LRP1), a ubiquitously expressed, highly glycosylated membrane receptor, as a conserved endogenous ligand for human DCIR and murine DCIR1. DCIR specifically interacts with LRP1 through galactose-terminated biantennary complex-type N-glycans. By combining X-ray crystallography, small angle X-ray scattering, and site-directed mutagenesis, we define the structural organization of DCIR as a dimeric receptor and the basis of DCIR-glycan recognition, revealing key contact residues and an atypical glycan-binding mode. 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