Proteoglycan research最新文献

{"title":"Introduction to the Special Issue on Proteoglycan and Glycosaminoglycan Biology.","authors":"Pyong Woo Park, Lianchun Wang","doi":"10.1002/pgr2.70050","DOIUrl":"10.1002/pgr2.70050","url":null,"abstract":"","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"4 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148690608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heparan Sulfate Proteoglycans in Immunity.","authors":"Moe Iwai, Pyong Woo Park","doi":"10.1002/pgr2.70048","DOIUrl":"10.1002/pgr2.70048","url":null,"abstract":"<p><p>In immune cells, heparin was first identified in mast cells in the 1940s, followed by the discovery of heparan sulfate in lymphocytes and granulocytes during the 1970s and 1980s. Subsequent decades of research have revealed how heparan sulfate and heparin, conjugated to core proteins as heparan sulfate proteoglycans (HSPGs), act as versatile modulators of immune function. It is now known that HSPGs are expressed by virtually all leukocytes and bind hundreds of immune mediators, including cytokines, proteases, growth factors, antimicrobial peptides, and extracellular matrix (ECM) components. HSPGs on leukocyte surfaces and within intracellular granules, as well as those on non-immune cells and within the ECM, shape immune cell development and responses to both endogenous and exogenous threats. Because immune activity must be tightly controlled to prevent collateral tissue damage, HSPGs play critical modulatory roles-facilitating, competing, protecting, presenting, or allosterically regulating immune factors. Consequently, mutations in HSPG core proteins and heparan sulfate biosynthetic enzymes, or dysregulation of HSPG-mediated immune interactions, contribute to diverse pathologies, including primary immunodeficiencies, autoimmune disease, infection, inflammatory tissue injury, allergy, and cancer. This review will highlight key mechanisms through which HSPGs regulate the development and function of major immune cell types.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"4 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13318413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148364361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MMP2 sheds Glypican-4 to suppress Slit3-Robo4 signaling and angiogenesis.","authors":"Wenyuan Xiao, Alexander R Orta, Jingwen Yue, Xuehong Song, Huquan Yin, Lianchun Wang","doi":"10.1002/pgr2.70044","DOIUrl":"10.1002/pgr2.70044","url":null,"abstract":"<p><p>Axon guidance molecules, initially identified for their roles in neural development, are now recognized as crucial regulators of angiogenesis and blood vessel patterning. Among these, Slit3 promotes endothelial cell migration, proliferation, and vascular network formation by signaling through the endothelial-specific receptor Robo4. This interaction depends on heparan sulfate (HS) as a co-receptor for assembly of the Slit3-Robo4 complex, although the specific HS proteoglycan involved has not yet been identified. Our recent work also shows that Robo4 ectodomain shedding by ADAM10 and ADAM17 suppresses this angiogenic pathway. Here, we identify matrix metalloproteinase-2 (MMP2) as an additional suppressor of Slit3-Robo4 signaling. <i>MMP2</i> expression correlates with <i>Slit3</i> in diaphragm mesenchymal and lung stromal cells and inhibits Slit3-induced endothelial cell proliferation, migration, and angiogenesis. Furthermore, we identify glypican-4 (GPC4) as an HS proteoglycan mediating Slit3-Robo4 co-receptor function and show that MMP2 cleaves GPC4, thereby disrupting Slit3-Robo4 signaling. These findings establish GPC4 as a vital co-receptor for Slit3-Robo4 signaling and reveal MMP2-mediated GPC4 shedding as a novel mechanism to regulate angiogenic responses. This study uncovers an additional level of proteolytic regulation in Slit3-Robo4 signaling-driven angiogenesis, broadening our understanding of how extracellular proteinases influence ligand-receptor/co-receptor interactions.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13480415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decorin Evokes a Pro-lysosomal Pathway in Lymphatic Endothelial Cells.","authors":"Gabriel J Pascal, Dipon K Mondal, Sadie Kim, Christopher Xie, Devanarayanan Siva Sankar, Jörn Dengjel, Renato V Iozzo","doi":"10.1002/pgr2.70038","DOIUrl":"10.1002/pgr2.70038","url":null,"abstract":"<p><p>The lymphatic system is critical to the body's immune and circulatory system, and lymphangiogenesis, the development of new lymphatic vessels from pre-existing ones is a significant process capitalized upon by cancer during tumorigenesis. Decorin is a small leucine-rich proteoglycan which we have previously shown to be anti-tumorigenic and a suppressor of lymphangiogenesis. We have also shown that decorin exercises its anticancer properties through its ability to evoke autophagy. Through a comprehensive and unbiased proteomic analysis, we explored the implications of decorin exposure on protein expression within mouse lymphatic endothelial cells. We discovered that decorin enriches several protein pathways, notably proteasomal degradation and lysosomal pathways. Several proteins within these pathways such as lysosome associated membrane protein 1 (Lamp1) and Neural precursor cell expressed developmentally downregulated protein 8 (Nedd8) were differentially regulated following decorin treatment. These proteins and their functional pathways should be considered therapeutic targets and emerge as candidates for further exploration within the context of decorin and cancer suppression.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12530112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145330737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epithelial Heparan Sulfate Promotes <i>Staphylococcus aureus</i> Corneal Infection by Inhibiting Cathelicidins.","authors":"Kazutaka Hayashida, Jeffrey D Esko, Richard D Gallo, Jian Liu, Winston W-Y Kao, Pyong Woo Park","doi":"10.1002/pgr2.70041","DOIUrl":"10.1002/pgr2.70041","url":null,"abstract":"<p><p>Cathelicidins are short cationic peptides with potent microbicidal activities and comprise an important arm of host innate immunity. Many cell types can produce cathelicidins, but they are mainly expressed by recruited immune cells and are induced in epithelial cells during infection. Although the mechanisms of bacterial killing by cathelicidins have been largely elucidated in vitro, those that regulate their activities in vivo are less well understood. Bacterial pathogens often co-opt host extracellular matrix (ECM) components and their functions to escape host defense; however, it is unclear whether such mechanisms exist against cathelicidins. Several studies have demonstrated that host heparan sulfate (HS) inhibits LL-37, the human cathelicidin, suggesting that bacteria might exploit HS to evade killing by cathelicidins. However, precisely how HS inhibits LL-37 and possibly other cathelicidins remains unknown, and the role of the HS-cathelicidin interaction in infectious disease has not been rigorously studied. Here, we found that deleting CRAMP, the murine cathelicidin, significantly increases the susceptibility of mice to <i>Staphylococcus aureus</i> corneal infection. We also determined that heparan compounds bind to CRAMP with low nanomolar affinity, the secondary structure of CRAMP is required for HS binding, and HS binding to CRAMP inhibits CRAMP binding to target bacterial cells. Furthermore, we found that heparan compounds inhibit the killing of <i>S. aureus</i> by cathelicidins derived from several mammalian species in a 2-<i>O</i>-sulfate-dependent manner. Additionally, we demonstrate for the first time that conditional deletion of HS2ST, the enzyme responsible for 2-<i>O</i>-sulfation of HS, in corneal epithelial cells significantly reduces the susceptibility of mice to corneal infection. Altogether, these data uncover an endogenous inhibition mechanism of cathelicidins where 2-<i>O</i>-sulfated epithelial HS tightly binds and neutralizes the antibacterial activity of cathelicidins.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12806164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145999938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Glycosaminoglycan-Dependent Interactome of Neurexin-1 in Human Fetal Glial Cells.","authors":"Meg Critcher, Han Wu, Yajing Lu, Mia L Huang","doi":"10.1002/pgr2.70039","DOIUrl":"10.1002/pgr2.70039","url":null,"abstract":"<p><p>Neurexins are synaptic adhesion molecules best characterized in neurons, where they regulate synapse assembly and function, with emerging evidence indicating they are also abundantly expressed by astrocytes. To elucidate the interactome of NRXN1α, we employed a proximity labeling strategy in cultured human fetal glial cells (SVG p12 cells). This approach enables the identification of transient and spatially restricted protein interactions, offering insights into the molecular environment of NRXN1α in glia. Further, we investigated how the presence and number of glycosaminoglycan (GAG) chains present on NRXN1α influence these interactions by generating glycosylation-deficient mutants at previously characterized GAG glycosites. Here, we show that the astrocytic NRXN1α interactome in SVG p12 cells consists of over 400 proteins, half of which are likely modulated by GAGs. Our findings provide a systems-level view of NRXN1α-associated proteins in fetal glia cultured in the absence of neurons and highlight the role of GAG valency in modulating its interactome.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12707391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Decorin in the Ocular Surface: Structure, Function, and Therapeutic Potential.","authors":"Kartik Goel, Anil Tiwari, Shruti Rathore, Swati Sood, Virender S Sangwan, Rajiv R Mohan","doi":"10.1002/pgr2.70034","DOIUrl":"10.1002/pgr2.70034","url":null,"abstract":"<p><p>The ocular surface, comprising the cornea, conjunctiva, and sclera, relies on a complex extracellular matrix (ECM) for structural support and functional integrity. Decorin (DCN), a small leucine-rich proteoglycan, a key ECM component involved in collagen fibrillogenesis, growth factor modulation, and cellular regulation, is essential for maintaining corneal transparency, wound healing, and preventing pathological fibrosis. DCN interacts with various target molecules, including transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR), influencing critical processes, such as cell proliferation, inflammation, and angiogenesis. These interactions underscore DCN's therapeutic potential in ocular disorders like corneal scarring, pterygium, and keratoconus. This review explores the structure, expression, and functions of DCN in the ocular surface, emphasizing its regulatory mechanisms and therapeutic potential. Recent advancements include gene therapy approaches, sustained release systems, and topical applications, each demonstrating significant promise in treating ocular surface diseases. Additionally, the review highlights the importance of DCN in ocular disorders, including congenital stromal corneal dystrophy (CSCD), KC, and pterygium. This review aims to elucidate the multifaceted roles of DCN, paving the way for innovative therapeutic strategies in ocular surface therapy. Future directions for DCN research involve advanced delivery mechanisms, gene editing technologies, and expanded studies on other ocular surfaces.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13411070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148623008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyaluronan Accumulates in Inflamed Lymph Nodes and Promotes B-Cell Activation.","authors":"Zhiwei Li, Nadine Nagy, Gernot Kaber, Payton L Marshall, Naomi L Haddock, Everett Meyer, Robert R Vernon, Manish J Butte, Ovijit Chaudhuri, Thomas N Wight, Paul L Bollyky","doi":"10.1002/pgr2.70031","DOIUrl":"10.1002/pgr2.70031","url":null,"abstract":"<p><p>The extracellular matrix component hyaluronan (HA) plays important roles in inflammation and immune regulation. However, its involvement in lymphoid tissue during autoreactive processes remains poorly understood. Here, using the DORmO mouse model of autoimmune diabetes, we demonstrate that HA progressively accumulates in lymph nodes and splenic germinal centers during disease development. This accumulation is accompanied by a shift from high to low molecular mass HA fragments. Through immunofluorescence microscopy, we observed extensive colocalization between HA deposits and B cells in germinal centers. Inhibition of HA synthesis using 4-methylumbelliferone (4-MU) increased lymph node stiffness. Treatment with 4-MU decreased immunoglobulin production and reduced B cell activation and differentiation into plasmablasts following immunization. These findings reveal a previously unrecognized role for HA in regulating B cell responses within lymphoid tissues during autoimmune reactions and suggest that targeting HA synthesis may represent a novel therapeutic strategy for conditions involving dysregulated B cell responses.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"3 3","pages":"e70031"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyaluronidases as Targets for the Treatment of Neurological Diseases.","authors":"Larry S Sherman, Barbara A Sorg, Steven Matsumoto, Weiping Su, Fatima Banine, Stephen A Back","doi":"10.1002/pgr2.70036","DOIUrl":"10.1002/pgr2.70036","url":null,"abstract":"<p><p>Hyaluronan (HA) is a glycosaminoglycan synthesized at the cell membrane that can exist in numerous states in the extracellular matrix, including in ternary complexes with proteoglycans such as aggrecan and neurocan. HA synthesis is elevated following a wide variety of insults to the central nervous system (CNS) including neuroinflammatory disease, ischemia, and various forms of dementia. Recent studies have demonstrated that, in conjunction with increased HA synthesis, the expression and activities of hyaluronidases that digest HA are also elevated in the injured CNS. While high molecular weight forms of HA have their own functions that can be disrupted by hyaluronidases, digestion products of HA generated by these hyaluronidases have their own, distinct biological activities that can impact recovery from CNS damage. Here, we review some of the conditions and diseases in which hyaluronidase activity can play a role in preventing CNS repair and discuss the potential ways that hyaluronidase inhibitors could be used as therapeutic agents.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12826556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146055356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet Hyaluronan Synthase 3 Regulates Thrombin Signaling and Adhesion to Fibrinogen Under Venous Shear.","authors":"Kimberly A Queisser, Lydia Smith, Gabriel Leung, Nansy Albtoush, Rebecca A Mellema, Aaron C Petrey","doi":"10.1002/pgr2.70035","DOIUrl":"10.1002/pgr2.70035","url":null,"abstract":"<p><p>Hyaluronan (HA) is an essential glycosaminoglycan with supportive roles in hematopoiesis. HA is synthesized by hyaluronan synthases (HAS1, HAS2, and HAS3) and plays a crucial role in cellular signaling and extracellular matrix interactions. Megakaryocytes (MKs), the platelet progenitor cell, express only HAS2 and HAS3, and dysregulated metabolism of HA by MKs leads to thrombocytopenia. To unravel the contribution of HAS3 in platelet function, Using HAS1/3 knockout (dKO) mice, we demonstrate that thrombin-mediated activation is significantly impaired, whereas collagen-dependent activation remains intact. Functional assays indicate that platelet aggregation, integrin α_IIbβ3 activation, and granule secretion are reduced in HAS1/3 KO platelets. However, tail bleeding times remain normal, suggesting that primary hemostasis is not severely affected. Under flow conditions, dKO platelet adhesion to fibrinogen is deficient under venous shear, while adhesion under arterial shear is unaffected. Mechanistically, these impairments correlate with reduced phosphorylation of AKT (p-AKT), while phosphorylation of PLCγ (p-PLCγ) remains preserved, suggesting that expression of HAS3 selectively regulates platelet function. These findings highlight HA synthesis as a novel regulator of thrombin-induced platelet activation and suggest that HAS enzymes may be previously unknown modulators of hemostatic and thrombotic responses.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12826595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146055284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}