About

Jeffrey Esko is a Professor of Cellular and Molecular Medicine at UC San Diego, located in the School of Medicine. His research focuses on the structure, biosynthesis, and function of proteoglycans. His laboratory conducts structural studies of heparan sulfate using mass spectrometry, develops animal models lacking key enzymes involved in proteoglycan assembly, and applies genome-wide methods to identify novel genes involved in heparan sulfate biosynthesis. His work also includes analyzing guanidinylated glycosides that bind to proteoglycans to facilitate delivery of high molecular weight cargo into cells for enzyme replacement therapy, as well as studying proteoglycans in lipoprotein metabolism in the liver and macrophages. Additionally, he investigates proteoglycan-associated receptors with an emphasis on the vasculature. Esko has extensive experience in the isolation and characterization of glycosaminoglycans, developing genetic models altered in glycosaminoglycan metabolism, and creating small molecule agents for treating disorders involving glycosaminoglycans. His contributions have been recognized through numerous awards, including the NIH MERIT award, the Society for Glycobiology Karl Meyer Award, and election as a Fellow of the AAAS.

Research topics

• Biology
• Internal medicine
• Virology
• Biochemistry
• Cell biology
• Medicine
• Chemistry
• Immunology

Selected publications

• GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling

  Nature · 2026-01-28 · 3 citations

  articleOpen access

  Heparan sulfate proteoglycans (HSPGs) have been recognized as key plasma membrane-tethered co-receptors for a broad range of growth factors and cytokines containing cationic heparan-binding domains1,2. However, how HSPGs mechanistically mediate signalling at the cell surface—particularly in the context of cell surface RNA—remain poorly understood. During developmental and disease processes, vascular endothelial growth factor (VEGF-A), a heparan sulfate-binding factor, regulates endothelial cell growth and angiogenesis3. The regulatory paradigm for endothelial cell-mediated selectively of VEGF-A binding and activity has largely been focused on understanding the selective sulfation of the anionic heparan sulfate chains4–8. Here we examine the organizational rules of a new class of anionic cell surface conjugates, glycoRNAs9,10, and cell surface RNA-binding proteins (csRBPs11,12). Leveraging genome-scale knockout screens, we discovered that heparan sulfate biosynthesis and specifically the 6-O-sulfated forms of heparan sulfate chains are critical for the assembly of clusters of glycoRNAs and csRBPs (cell surface ribonucleoproteins (csRNPs)). Mechanistically, we show that these clusters antagonize heparan sulfate-mediated activation of ERK signalling downstream of VEGF-A. We demonstrate that the heparan sulfate-binding domain of VEGF-A165 is responsible for binding RNA, and that disrupting this interaction enhances ERK signalling and impairs vascular development both in vitro and in vivo and is conserved across species. Our study thus uncovers a previously unrecognized regulatory axis by which csRNPs negatively modulate heparan sulfate-mediated signalling in the context of angiogenesis driven by VEGF-A. Heparan sulfate proteoglycans facilitate the assembly of clusters of glycoRNAs and cell surface RNA-binding proteins, which negatively modulate VEGF-A signalling and angiogenesis.

  PublisherDOI

• Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis

  Nature Cell Biology · 2026-02-11 · 2 citations

  articleOpen access

  Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.

  PublisherDOI

• Multi-omic analysis reveals the unique glycan landscape of the blood-brain barrier glycocalyx

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-07 · 7 citations

  preprintOpen access

  The blood-brain barrier (BBB) glycocalyx is the dense layer of glycans and glycoconjugates that coats the luminal surface of the central nervous system (CNS) vasculature. Despite being the first point of contact between the blood and brain, not much is known about the BBB glycocalyx. Here, we performed a multi-omic investigation of the BBB glycocalyx which revealed a unique glycan landscape characterized by enrichment of sialic acid, chondroitin sulfate, and hyaluronan. We found that the BBB glycocalyx was thicker than glycocalyces in the peripheral vasculature and that hyaluronan was the major contributor to its ultrastructure. Using endothelial RNA sequencing, we found potential genetic determinants for these differences, including BBB enrichment of genes involved in sialic acid addition and peripheral enrichment of Tmem2 and Hyal2, the only known cell-surface hyaluronidases. Glycocalyx degradation and increases in vascular permeability are widely associated with inflammation. However, we found that the BBB glycocalyx remains largely unchanged in neuroinflammation during the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and that its degradation is not sufficient to alter BBB permeability in health. Moreover, we showed that CNS endothelial sialic acid removal delays onset of EAE, indicating that BBB glycocalyx sialic acid may contribute to the progression of neuroinflammation. These findings underscore the unique and robust nature of the BBB glycocalyx and provide targets and tools for future studies into its role in health and neuroinflammation.

  PublisherOA PDFDOI

• SARS-CoV-2 infectivity can be modulated through bacterial grooming of the glycocalyx

  mBio · 2025-02-25 · 2 citations

  articleOpen access

  ABSTRACT The gastrointestinal (GI) tract is a site of replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and GI symptoms are often reported by patients. SARS-CoV-2 cell entry depends upon heparan sulfate (HS) proteoglycans, which commensal bacteria that bathe the human mucosa are known to modify. To explore human gut HS-modifying bacterial abundances and how their presence may impact SARS-CoV-2 infection, we developed a task-based analysis of proteoglycan degradation on large-scale shotgun metagenomic data. We observed that gut bacteria with high predicted catabolic capacity for HS differ by age and sex, factors associated with coronavirus disease 2019 (COVID-19) severity, and directly by disease severity during/after infection, but do not vary between subjects with COVID-19 comorbidities or by diet. Gut commensal bacterial HS-modifying enzymes reduce spike protein binding and infection of authentic SARS-CoV-2, suggesting that bacterial grooming of the GI mucosa may impact viral susceptibility. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019, can infect the gastrointestinal (GI) tract, and individuals who exhibit GI symptoms often have more severe disease. The GI tract’s glycocalyx, a component of the mucosa covering the large intestine, plays a key role in viral entry by binding SARS-CoV-2’s spike protein via heparan sulfate (HS). Here, using metabolic task analysis of multiple large microbiome sequencing data sets of the human gut microbiome, we identify a key commensal human intestinal bacteria capable of grooming glycocalyx HS and modulating SARS-CoV-2 infectivity in vitro . Moreover, we engineered the common probiotic Escherichia coli Nissle 1917 (EcN) to effectively block SARS-CoV-2 binding and infection of human cell cultures. Understanding these microbial interactions could lead to better risk assessments and novel therapies targeting viral entry mechanisms.

  PublisherDOI

• Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis

  Journal of Clinical Investigation · 2025-09-09 · 3 citations

  articleOpen accessSenior author

  3-O-sulfation of heparan sulfate (HS) is the key determinant for binding and activation of antithrombin III (AT). This interaction is the basis of heparin treatment to prevent thrombotic events and excess coagulation. Antithrombin-binding HS (HSAT) is expressed in human tissues but is thought to be expressed in the subendothelial space, mast cells, and follicular fluid. Here, we show that HSAT is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues. In the pancreas, HSAT is expressed by healthy ductal cells, and its expression is increased in premalignant pancreatic intraepithelial neoplasia lesions but not in pancreatic ductal adenocarcinoma (PDAC). Inactivation of HS3ST1, a key enzyme in HSAT synthesis, in PDAC cells eliminated HSAT expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse PDAC model. HSAT-positive PDAC cells bind AT, which inhibits the generation of active thrombin by tissue factor and factor VIIa. Furthermore, plasma from patients with PDAC showed accumulation of HSAT, suggesting its potential as a marker of tumor formation. These findings suggest that HSAT exerts a tumor-suppressing function through recruitment of AT and that the decrease in HSAT during progression of pancreatic tumorigenesis increases inflammation and metastatic potential.

  PublisherDOI

• Release of Extracellular Matrix Components after Human Traumatic Brain Injury

  eNeuro · 2025-06-01 · 1 citations

  articleOpen access

  Animal studies and human tissue experiments have demonstrated that traumatic brain injury (TBI) causes damage to the extracellular matrix (ECM). To test the hypothesis that TBI causes disruption of sulfated glycosaminoglycan (sGAG) in the ECM, we measured levels of sGAG in the cerebrospinal fluid (CSF), blood, and urine, in patients with severe TBI in the acute postinjury period. Samples of CSF, blood, and urine were obtained within 72 h of injury in patients who received external ventricular drains as part of their treatment of severe TBI. Levels of chondroitin and heparan sGAGs were measured, along with their disaccharide constituents. Demographic information, presence of polytrauma, brain injury load, and distance of radiologically visible parenchymal injury from the ventricle were analyzed for correlation with total subtype sGAG levels. Levels were measured in 14 patients ranging in age from 17 to 90 years. CSF sGAG levels were variable among patients, with higher sGAG levels in plasma compared with CSF. Patients with polytrauma had nonsignificantly higher blood sGAG compared with patients with isolated head injury. Subcategories of CSF sGAG levels correlated with distance from the ventricle of parenchymal injury but not with brain injury load. This study is the first to measure sGAG levels in ventricular CSF and the first to analyze levels in TBI. These data demonstrate the elevation locally of intracranial sGAGs after severe TBI and suggest rapid local metabolism of these breakdown products. The consequences of ECM breakdown may provide unique therapeutic and preventive avenues to mitigate postinjury sequelae.

  PublisherOA PDFDOI

• Novel Application of T1ρ Magnetic Resonance Imaging for Noninvasive Assessment of Bladder Hyperpermeability Biomarkers: A Focus on Glycosaminoglycan Content

  Neurourology and Urodynamics · 2025-05-04

  article

  PURPOSE: Bladder wall hyperpermeability due to glycosaminoglycan depletion is implicated in interstitial cystitis/bladder pain syndrome pathogenesis. This study sought to validate T1ρ MRI as a noninvasive imaging sequence for assessing bladder wall hyperpermeability biomarkers, with a focus on bladder glycosaminoglycan content, in protamine sulfate-induced models of interstitial cystitis/bladder pain syndrome. MATERIALS AND METHODS: Rat bladders (n = 8) treated with saline (control), protamine sulfate, pentosan polysulfate, or protamine sulfate + pentosan polysulfate (rescue) were imaged in situ using T1ρ and standard MRI sequences. Predominant bladder glycosaminoglycans, chondroitin and heparan sulfate, were measured in subsequently harvested rat bladders via aniline tagging coupled with mass spectrometry. Human bladder biopsies (n = 12) were similarly imaged before and after protamine sulfate treatment, and post-imaging glycosaminoglycan analysis was performed. Data were compared between groups using one-way ANOVA or paired Student t-test. T1ρ relaxivity was correlated with chemically measured glycosaminoglycan content using linear regression. RESULTS: Protamine sulfate-treated rat bladders had decreased glycosaminoglycans and higher T1ρ relaxivity relative to controls. Pentosan polysulfate also decreased glycosaminoglycans versus controls and did not mitigate protamine-mediated glycosaminoglycan depletion. Importantly, T1ρ relaxivity correlated with chemical glycosaminoglycan quantification (chondroitin sulfate: r = 0.86, p < 0.01; heparan sulfate r = 0.80, p = 0.02). In human biopsies, T1ρ relaxivity increased after protamine sulfate treatment versus baseline (154.2 ± 5.9 vs. 131.0 ± 4.4 ms, p < 0.001), consistent with decreased glycosaminoglycans, while chemical analyses failed to capture statistically significant changes in bladder glycosaminoglycans. CONCLUSIONS: T1ρ MRI accurately measured glycosaminoglycans in rat bladders and differentiated protamine sulfate-treated bladder biopsies from unperturbed specimens in humans. T1ρ MRI warrants further investigation as a novel biomarker of bladder glycosaminoglycan content in interstitial cystitis/bladder pain syndrome.

  PublisherDOI

• Tumor Acidosis Remodels the Glycocalyx to Control Lipid Scavenging and Ferroptosis

  Research Square · 2025-07-11

  preprintOpen access
  PublisherOA PDFDOI

• Bruch’s membrane heparan sulfate retains lipoproteins in the early stages of age-related macular degeneration

  Proceedings of the National Academy of Sciences · 2025-06-13 · 5 citations

  articleOpen accessSenior author

  Lipoprotein retention in Bruch's membrane is a key event in the pathobiology of early and intermediate age-related macular degeneration (AMD). However, the mechanism of lipoprotein retention in BrM is unknown. Given the established role of glycosaminoglycans (GAG) in binding lipoproteins, our laboratory sought to determine the role of GAGs in AMD BrM. In this study, BrM GAG content in AMD pathobiology was analyzed in human postmortem tissue. Strikingly, increased levels of highly sulfated heparan sulfate were present in AMD Bruch's membrane as compared to non-AMD samples. In addition, using scanning electron microscopy of postmortem AMD tissue, we show aggregates of lipoprotein-like particles on the retinal pigmented epithelium side of Bruch's membrane adjacent to heparan sulfate. We also show that heparin displaces lipoproteins rich in apolipoprotein A1 from human BrM, suggesting their identity as high-density lipoproteins. Using human BrM immobilized to quartz crystal microbalance biosensor (QCM) chips, we show that heparan sulfate is required for lipoprotein binding to BrM and soluble heparan sulfate can remove lipoproteins bound to BrM. Thus, our data establish that heparan sulfate regulates lipoprotein deposition in AMD BrM. These findings provide a foundation for targeted therapies capable of either preventing lipoprotein accumulation or removing drusen in the early and intermediate stages of AMD prior to vision loss.

  PublisherOA PDFDOI

• Endothelial Glycocalyx Turnover in Vascular Health and Disease: Rethinking Endothelial Dysfunction

  Annual Review of Biochemistry · 2025-03-25 · 30 citations

  reviewOpen accessSenior author

  The endothelial glycocalyx, a glycan-rich layer on the luminal surface of endothelial cells lining blood and lymphatic vessels, plays a crucial role in vascular homeostasis by regulating vascular permeability, immune cell trafficking, and vascular tone. Dysregulated endothelial glycocalyx turnover-whether through altered synthesis, intracellular degradation, or shedding-contributes to endothelial dysfunction in conditions such as sepsis, ischemic events, and chronic inflammatory disorders including diabetes and atherosclerosis. In this review, we examine the structure, function, and turnover of the endothelial glycocalyx, emphasizing how pathological changes in its turnover drive vascular dysfunction. We also highlight diagnostic approaches to evaluate dysregulated endothelial glycocalyx turnover in connection with vascular diseases and discuss therapeutic strategies aimed at preventing endothelial glycocalyx degradation and restoring endothelial function.

  PublisherDOI

Recent grants

• CORE D - Proteomics Core

  NIH · $52.4M · 2016–2026

• NIH Grant R21HD052920

  NIH · $348k · 2009

• NIH Grant R01CA046462

  NIH · $2.1M · 2002

• UCSD Biomedical Scientist Career Development Program in Glycoscience

  NIH · $5.3M · 2018–2024

• NIH Grant R13AR069987

  NIH · $25k · 2017

Frequent coauthors

• Jamey D. Marth

  Sanford Burnham Prebys Medical Discovery Institute

  66 shared

• Patricia Dickson

  62 shared

• Yu Yamaguchi

  Gunma Children's Medical Center

  59 shared

• Maurizio Pacifici

  56 shared

• David M. Ornitz

  Washington University in St. Louis

  52 shared

• C Merry

  52 shared

• Andrea Vortkamp

  University of Duisburg-Essen

  52 shared

• Joanna Phillips

  52 shared

Education

• Ph.D., Cellular and Molecular Medicine

  University of California, San Diego

  1995

• B.S., Biology

  University of California, San Diego

  1989

Awards & honors

• NIH MERIT award (1999 - 2009)
• Society for Glycobiology Karl Meyer Award (2007)
• Uppsala University Doctor of Medicine (honoris causa) (2010)
• International Glycoconjugate Organization IGO award (2011)
• American Association for the Advancement of Science Elected…