{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T15:56:36Z","timestamp":1793980596542,"version":"4.8.0"},"reference-count":77,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35-GM147039"],"award-info":[{"award-number":["R35-GM147039"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000884","name":"Cancer Research Institute","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000884","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005326","name":"Yale University","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100005326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023581","name":"National Science Foundation Graduate Research Fellowship Program","doi-asserted-by":"publisher","award":["DGE-2139841"],"award-info":[{"award-number":["DGE-2139841"]}],"id":[{"id":"10.13039\/100023581","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The endogenous tear peptidome plays essential roles in maintaining ocular homeostasis by stimulating immune response and participating in antimicrobial activity. The biological function of these native peptides is governed by their biochemical properties, including peptide length, charge, and hydrophobicity. Accordingly, the production of native peptides within the tear film is tightly regulated through a complex interplay between circulating proteases and the proteolytic susceptibility of the protein substrate. Though glycosylation has been shown to regulate the proteolysis of specific proteins in vitro, the extent to which endogenous cleavage motifs are mediated by proximal O-glycans remains unexplored in a complex biofluid. Furthermore, the existence and identity of native tear peptides bearing O-glycans have yet to be elucidated, largely due to the high analytical complexity of tear fluid and the difficulty in characterizing O-glycosylated peptides. To address this gap, we leveraged advances in mass spectrometry (MS) to provide the first observation of extracellular tear O-glycopeptides, detailing their biochemical properties and overall glycan compositions. Beyond systematic profiling of the O-glycopeptidome, we employed site-specific glycoproteomic analysis followed by molecular dynamics to investigate the correlation between O-glycan proximity and proteolysis. Here, we observed that O-glycans preferentially occupy glycosites distal from the N-\/C-terminus, which was associated with distinct cleavage motifs and peptide backbones. We then showed in silico that O-glycosylation on lacritin can mediate the solvent accessibility of proximal cleavage residues, thus providing a structural basis for these observations. Finally, cleavage studies of glycosylated and nonglycosylated lacritin revealed that the unmodified form exhibited significantly greater degradation by endogenous tear proteases, supporting a protective role for its glycans. Taken together, this study defines the proteolytic landscape at the ocular surface and highlights a potential role for tear fluid O-glycans in mediating proteolysis.<\/jats:p>","DOI":"10.1021\/jacsau.6c00834","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:34:12Z","timestamp":1782174852000},"page":"4321-4335","source":"Crossref","is-referenced-by-count":3,"title":["O-Glycosylation\nShapes the Proteolytic Landscape\nof the Native Tear Peptidome"],"prefix":"10.1021","volume":"6","author":[{"given":"Vincent","family":"Chang","sequence":"first","affiliation":[{"name":"Yale University , , 225 Prospect St , , ,","place":["New Haven, Connecticut, United States, 06511"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J.","family":"Chen","sequence":"additional","affiliation":[{"name":"Yale University , , 225 Prospect St , , ,","place":["New Haven, Connecticut, United States, 06511"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Lian","sequence":"additional","affiliation":[{"name":"Yale University , , 225 Prospect St , , ,","place":["New Haven, Connecticut, United States, 06511"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4561-9838","authenticated-orcid":true,"given":"Keira E.","family":"Mahoney","sequence":"additional","affiliation":[{"name":"Yale University , , 225 Prospect St , , ,","place":["New Haven, Connecticut, United States, 06511"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2382-5067","authenticated-orcid":true,"given":"Stacy A.","family":"Malaker","sequence":"additional","affiliation":[{"name":"Yale University , , 225 Prospect St , , ,","place":["New Haven, Connecticut, United States, 06511"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"issue":"4","key":"2026072709072966700_cit1","doi-asserted-by":"publisher","first-page":"1979","DOI":"10.1167\/iovs.10-6997d","article-title":"The International\nWorkshop on Meibomian\nGland Dysfunction: Report of the Subcommittee on Tear Film Lipids\nand Lipid-Protein Interactions in Health and Disease","volume":"52","author":"Green-Church","year":"2011","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"issue":"46","key":"2026072709072966700_cit2","doi-asserted-by":"publisher","first-page":"8131","DOI":"10.1039\/C4TB00979G","article-title":"Lacritin-Mediated\nRegeneration of the Corneal Epithelia\nby Protein Polymer Nanoparticles","volume":"2","author":"Wang","year":"2014","journal-title":"J. Mater.\nChem. B"},{"issue":"1","key":"2026072709072966700_cit3","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.biochi.2008.07.007","article-title":"Role of Lactoferrin in the Tear Film","volume":"91","author":"Flanagan","year":"2009","journal-title":"Biochimie"},{"issue":"12","key":"2026072709072966700_cit4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0051979","article-title":"Lacrimal Proline Rich 4 (LPRR4) Protein\nin the Tear\nFluid Is a Potential Biomarker of Dry Eye Syndrome","volume":"7","author":"Aluru","year":"2012","journal-title":"PLoS One"},{"key":"2026072709072966700_cit5","doi-asserted-by":"publisher","first-page":"S70","DOI":"10.1097\/ICL.0000000000000641","article-title":"Tear Proteases\nand Protease Inhibitors: Potential Biomarkers and Disease Drivers\nin Ocular Surface Disease","volume":"46","author":"Fu","year":"2020","journal-title":"Eye Contact Lens"},{"issue":"5","key":"2026072709072966700_cit6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2025.108455","article-title":"Lacritin\nCleavage-Potentiated Targeting of Iron - Respiratory Reciprocity Promotes\nBacterial Death","volume":"301","author":"Gh","year":"2025","journal-title":"J. Biol. Chem."},{"key":"2026072709072966700_cit7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01221","article-title":"The Biology of Lactoferrin, an Iron-Binding\nProtein That Can Help Defend Against Viruses and Bacteria","volume":"11","author":"Kell","year":"2020","journal-title":"Front. Immunol."},{"issue":"12","key":"2026072709072966700_cit8","doi-asserted-by":"publisher","first-page":"3423","DOI":"10.1046\/j.1432-1327.2001.02241.x","article-title":"Proteolytic Processing\nof a Human Salivary Proline-Rich\nProtein Precursor by Proprotein Convertases","volume":"268","author":"Chan","year":"2001","journal-title":"Eur. J. Biochem."},{"issue":"6","key":"2026072709072966700_cit9","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.tibs.2025.03.014","article-title":"Understanding Peptide Hormones: From\nPrecursor Proteins to Bioactive Molecules","volume":"50","author":"Coassolo","year":"2025","journal-title":"Trends\nBiochem. Sci."},{"issue":"4","key":"2026072709072966700_cit10","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1111\/bph.15508","article-title":"Protective\nProperties of GLP-1 and Associated Peptide Hormones in Neurodegenerative\nDisorders","volume":"179","author":"Ho\u0308lscher","year":"2022","journal-title":"Br. J. Pharmacol."},{"issue":"1","key":"2026072709072966700_cit11","doi-asserted-by":"publisher","DOI":"10.1038\/s43586-023-00205-2","article-title":"Peptidomics","volume":"3","author":"Hellinger","year":"2023","journal-title":"Nat. Rev. Methods\nPrimer"},{"key":"2026072709072966700_cit12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.015833","article-title":"Lacritin Proteoforms\nPrevent Tear\nFilm Collapse and Maintain Epithelial Homeostasis","volume":"296","author":"Georgiev","year":"2021","journal-title":"J. Biol. Chem."},{"issue":"1","key":"2026072709072966700_cit13","doi-asserted-by":"publisher","DOI":"10.1038\/s43586-022-00128-4","article-title":"Glycoproteomics","volume":"2","author":"Bagdonaite","year":"2022","journal-title":"Nat. Rev. Methods\nPrimer"},{"issue":"3","key":"2026072709072966700_cit14","doi-asserted-by":"publisher","DOI":"10.3390\/biom14030282","article-title":"N-Glycosylation as\na Modulator of Protein Conformation\nand Assembly in Disease","volume":"14","author":"Pasala","year":"2024","journal-title":"Biomolecules"},{"issue":"6","key":"2026072709072966700_cit15","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1038\/s41589-023-01539-4","article-title":"Immobilized Enzyme Cascade for Targeted Glycosylation","volume":"20","author":"Makrydaki","year":"2024","journal-title":"Nat. Chem. 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Chem."},{"key":"2026072709072966700_cit19","doi-asserted-by":"publisher","first-page":"7949","DOI":"10.1021\/acs.jcim.4c00613","article-title":"Breaking Down the Bottlebrush: Atomically-Detailed\nStructural Dynamics of Mucins","volume":"64","author":"Kearns","year":"2024","journal-title":"J. Chem. Inf.\nModel."},{"issue":"47","key":"2026072709072966700_cit20","doi-asserted-by":"publisher","first-page":"14623","DOI":"10.1073\/pnas.1511175112","article-title":"A Systematic Study of Modulation of ADAM-Mediated Ectodomain\nShedding by Site-Specific O-Glycosylation","volume":"112","author":"Goth","year":"2015","journal-title":"Proc.\nNatl. Acad. Sci. 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Cell Res."},{"issue":"1","key":"2026072709072966700_cit23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2000080","article-title":"Proteolytic Origin of the Soluble\nHuman IL-6R In Vivo and a Decisive Role of N-Glycosylation","volume":"15","author":"Riethmueller","year":"2017","journal-title":"PLOS Biol."},{"key":"2026072709072966700_cit24","doi-asserted-by":"publisher","DOI":"10.1038\/srep46174","article-title":"Mechanistic\nInsights into Ectodomain\nShedding: Susceptibility of CADM1 Adhesion Molecule Is Determined\nby Alternative Splicing and O-Glycosylation","volume":"7","author":"Shirakabe","year":"2017","journal-title":"Sci. Rep."},{"key":"2026072709072966700_cit25","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/s41574-025-01125-9","article-title":"Amylin: emergent therapeutic\nopportunities in overweight, obesity and diabetes mellitus","volume":"21","author":"Walker","year":"2025","journal-title":"Nat. Rev. Endocrinol."},{"issue":"25","key":"2026072709072966700_cit26","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adx8201","article-title":"Chemical synthesis uncovers\nthe significant impact of natural glycosylation on islet amyloid polypeptide\naggregation","volume":"11","author":"Li","journal-title":"Sci. Adv."},{"key":"2026072709072966700_cit27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17473-1","article-title":"An Atlas\nof O-Linked Glycosylation on Peptide Hormones Reveals Diverse Biological\nRoles","volume":"11","author":"Madsen","year":"2020","journal-title":"Nat. Commun."},{"issue":"20","key":"2026072709072966700_cit28","doi-asserted-by":"publisher","first-page":"7629","DOI":"10.1074\/jbc.RA118.001978","article-title":"TAILS N-Terminomics\nand Proteomics Reveal Complex Regulation of Proteolytic Cleavage by\nO-Glycosylation","volume":"293","author":"King","year":"2018","journal-title":"J. Biol. Chem."},{"issue":"17","key":"2026072709072966700_cit29","doi-asserted-by":"publisher","first-page":"9184","DOI":"10.1021\/acs.analchem.7b01926","article-title":"Targeted Mass Spectrometry\nApproach Enabled Discovery of O-Glycosylated Insulin and Related Signaling\nPeptides in Mouse and Human Pancreatic Islets","volume":"89","author":"Yu","year":"2017","journal-title":"Anal. Chem."},{"issue":"4","key":"2026072709072966700_cit30","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1021\/acs.jproteome.9b00592","article-title":"Profiling\nof Endogenously Intact N-Linked and O-Linked\nGlycopeptides from Human Serum Using an Integrated Platform","volume":"19","author":"Wang","year":"2020","journal-title":"J. Proteome Res."},{"issue":"6","key":"2026072709072966700_cit31","doi-asserted-by":"publisher","first-page":"2649","DOI":"10.1021\/acs.jproteome.5b00179","article-title":"Human Basal Tear Peptidome Characterization by CID,\nHCD, and ETD Followed by in Silico and in Vitro Analyses for Antimicrobial\nPeptide Identification","volume":"14","author":"Azkargorta","year":"2015","journal-title":"J. Proteome Res."},{"key":"2026072709072966700_cit32","doi-asserted-by":"publisher","first-page":"4728","DOI":"10.1021\/acs.analchem.4c06750","article-title":"Recent Advances in Mass Spectrometry-Based\nBottom-Up Proteomics","volume":"97","author":"Movassaghi","year":"2025","journal-title":"Anal. Chem."},{"issue":"10","key":"2026072709072966700_cit33","doi-asserted-by":"publisher","first-page":"1866","DOI":"10.1021\/acschembio.1c00384","article-title":"Mucinomics as the\nNext Frontier of Mass Spectrometry","volume":"16","author":"Rangel-Angarita","year":"2021","journal-title":"ACS Chem.\nBiol."},{"key":"2026072709072966700_cit34","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2022.102174","article-title":"ScienceDirect Current\nStrategies\nfor Characterization of Mucin-Domain Glycoproteins","volume":"69","author":"Ince","year":"2022","journal-title":"Curr. Opin. Chem. Biol."},{"issue":"13","key":"2026072709072966700_cit35","doi-asserted-by":"publisher","first-page":"5242","DOI":"10.1021\/acs.analchem.3c05762","article-title":"Mass Spectrometry-Compatible\nElution Technique Enables an Improved Mucin-Selective Enrichment Strategy\nto Probe the Mucinome","volume":"96","author":"Mahoney","year":"2024","journal-title":"Anal. Chem."},{"issue":"43","key":"2026072709072966700_cit36","doi-asserted-by":"publisher","first-page":"23751","DOI":"10.1021\/acs.analchem.5c02666","article-title":"GlycoFASP: A Universal Method to\nPrepare Complex Mixtures for O-Glycoproteomic Analysis","volume":"97","author":"Finn","year":"2025","journal-title":"Anal. Chem."},{"issue":"9","key":"2026072709072966700_cit37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2025.110580","article-title":"In-Depth Analysis\nof the Tear Fluid Glycoproteome Reveals Diverse Lacritin Glycosylation\nand Spliceoforms","volume":"301","author":"Chang","year":"2025","journal-title":"J. Biol. Chem."},{"issue":"1","key":"2026072709072966700_cit38","doi-asserted-by":"publisher","DOI":"10.1038\/s43586-022-00128-4","article-title":"Glycoproteomics","volume":"2","author":"Bagdonaite","year":"2022","journal-title":"Nat. Rev. Methods\nPrimer"},{"issue":"12","key":"2026072709072966700_cit39","doi-asserted-by":"publisher","first-page":"6024","DOI":"10.1021\/pr500898r","article-title":"Assignment of Saccharide Identities\nthrough Analysis of Oxonium Ion Fragmentation Profiles in LC-MS\/MS\nof Glycopeptides","volume":"13","author":"Halim","year":"2014","journal-title":"J. Proteome Res."},{"issue":"10","key":"2026072709072966700_cit40","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22105369","article-title":"Oxonium\nIon Guided Analysis of Quantitative Proteomics\nData Reveals Site-Specific o-Glycosylation of Anterior Gradient Protein\n2 (Agr2)","volume":"22","author":"Pirro","year":"2021","journal-title":"Int. J. Mol. Sci."},{"issue":"12","key":"2026072709072966700_cit41","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2025.101085","article-title":"Extracting Informative\nGlycan-Specific Ions From Glycopeptide MS\/MS Spectra With GlyCounter","volume":"24","author":"Kothlow","year":"2025","journal-title":"Mol. Cell. Proteomics"},{"issue":"9","key":"2026072709072966700_cit42","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1021\/jacsau.3c00264","article-title":"False-Positive Glycopeptide\nIdentification via In-FAIMS\nFragmentation","volume":"3","author":"Rangel-Angarita","year":"2023","journal-title":"JACS Au"},{"issue":"2","key":"2026072709072966700_cit43","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1021\/pr300955f","article-title":"In-Source\nFragmentation and the Sources of Partially Tryptic Peptides in Shotgun\nProteomics","volume":"12","author":"Kim","year":"2013","journal-title":"J. Proteome Res."},{"issue":"8","key":"2026072709072966700_cit44","doi-asserted-by":"publisher","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A\nGraphical Gene-Set Enrichment\nTool for Animals and Plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"2026072709072966700_cit45","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.exer.2013.05.020","article-title":"Lacritin and the Tear Proteome as\nNatural Replacement Therapy for Dry Eye","volume":"117","author":"Karnati","year":"2013","journal-title":"Exp.\nEye Res."},{"issue":"33","key":"2026072709072966700_cit46","doi-asserted-by":"publisher","first-page":"21000","DOI":"10.1021\/acs.jafc.5c00821","article-title":"The Ability\nof Basic and Glycosylated Proline-Rich Proteins to Protect Oral Enzymes\nfrom Polyphenol Inhibition","volume":"73","author":"Proskura","year":"2025","journal-title":"J. Agric. Food Chem."},{"issue":"9","key":"2026072709072966700_cit47","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/S0003-9969(98)00040-5","article-title":"Interaction\nof Tannin with Human Salivary Proline-Rich\nProteins","volume":"43","author":"Lu","year":"1998","journal-title":"Arch. Oral Biol."},{"issue":"32","key":"2026072709072966700_cit48","doi-asserted-by":"publisher","first-page":"22172","DOI":"10.1074\/jbc.M114.570143","article-title":"A Cleavage-Potentiated\nFragment of Tear Lacritin Is Bactericidal","volume":"289","author":"McKown","year":"2014","journal-title":"J.\nBiol. Chem."},{"key":"2026072709072966700_cit49","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.10555","article-title":"Macrel: Antimicrobial Peptide Screening\nin Genomes and Metagenomes","volume":"8","author":"Santos-Ju\u0301nior","year":"2020","journal-title":"PeerJ."},{"issue":"D1","key":"2026072709072966700_cit50","doi-asserted-by":"publisher","first-page":"D1094","DOI":"10.1093\/nar\/gkv1051","article-title":"CAMPR3: A\nDatabase on Sequences, Structures and Signatures of Antimicrobial\nPeptides","volume":"44","author":"Waghu","year":"2016","journal-title":"Nucleic Acids Res."},{"issue":"16","key":"2026072709072966700_cit51","doi-asserted-by":"publisher","first-page":"2740","DOI":"10.1093\/bioinformatics\/bty179","article-title":"Deep Learning\nImproves Antimicrobial\nPeptide Recognition","volume":"34","author":"Veltri","year":"2018","journal-title":"Bioinformatics"},{"key":"2026072709072966700_cit52","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jprot.2015.09.009","article-title":"The Intriguing Heterogeneity\nof Human Salivary Proline-Rich Proteins: Short Title: Salivary Proline-Rich\nProtein Species","volume":"134","author":"Manconi","year":"2016","journal-title":"J. Proteomics"},{"issue":"26","key":"2026072709072966700_cit53","doi-asserted-by":"publisher","first-page":"17358","DOI":"10.1016\/S0021-9258(19)47381-X","article-title":"Structure\nand Bacterial Receptor Activity of a Human Salivary Proline-Rich Glycoprotein","volume":"266","author":"Gillece-Castro","year":"1991","journal-title":"J. Biol. Chem."},{"issue":"9","key":"2026072709072966700_cit54","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1038\/s41589-023-01293-7","article-title":"Structural Basis\nfor Translation Inhibition by the Glycosylated Drosocin Peptide","volume":"19","author":"Koller","year":"2023","journal-title":"Nat. Chem. Biol."},{"issue":"2","key":"2026072709072966700_cit55","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1042\/bj3100651","article-title":"A Novel Antibacterial\nPeptide Family Isolated from\nthe Silkworm, Bombyx Mori","volume":"310","author":"Hara","year":"1995","journal-title":"Biochem. J."},{"issue":"22","key":"2026072709072966700_cit56","doi-asserted-by":"publisher","first-page":"7394","DOI":"10.1021\/bi00022a012","article-title":"Insect Immunity. The\nInducible Antibacterial\nPeptide Diptericin Carries Two O-Glycans Necessary for Biological\nActivity","volume":"34","author":"Bulet","year":"1995","journal-title":"Biochemistry"},{"issue":"45","key":"2026072709072966700_cit57","doi-asserted-by":"publisher","first-page":"28533","DOI":"10.1074\/jbc.271.45.28533","article-title":"Antibacterial\nActivity of Glycosylated and Phosphorylated Chromogranin A-Derived\nPeptide 173\u2013194 from Bovine Adrenal Medullary Chromaffin Granules","volume":"271","author":"Strub","year":"1996","journal-title":"J. Biol. 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