Glycobiology and Extracellular Matrices
Sirtuin 1 reduces hyaluronan synthase 2 expression by inhibiting nuclear translocation of NF-κB and expression of the long-noncoding RNA HAS2–AS1
Hyaluronan (HA) is one of the most prevalent glycosaminoglycans of the vascular extracellular matrix (ECM). Abnormal HA accumulation within blood vessel walls is associated with tissue inflammation and is prominent in most vascular pathological conditions such as atherosclerosis and restenosis. Hyaluronan synthase 2 (HAS2) is the main hyaluronan synthase enzyme involved in HA synthesis and uses cytosolic UDP-glucuronic acid and UDP-GlcNAc as substrates. The synthesis of UDP-glucuronic acid can alter the NAD+/NADH ratio via the enzyme UDP-glucose dehydrogenase, which oxidizes the alcohol group at C6 to the COO− group.Heparin affects cytosolic glucose responses of hyperglycemic dividing mesangial cells
Mesangial expansion underlies diabetic nephropathy, leading to sclerosis and renal failure. The glycosaminoglycan heparin inhibits mesangial cell growth, but the molecular mechanism is unclear. Here, rat mesangial cells (RMCs) were growth-arrested in the G0/G1 phase of cell division, stimulated to divide in normal glucose (5.6 mm) or high glucose (25.6 mm) with or without heparin, and analyzed for glucose uptake. We observed that RMCs entering the G1 phase in normal glucose with or without heparin rapidly cease glucose uptake.The journey of hyaluronan research in the Journal of Biological Chemistry
Hyaluronan has a very simple structure. It is a linear glycosaminoglycan composed of disaccharide units of GlcNAc and d-glucuronic acid with alternating β-1,4 and β-1,3 glycosidic bonds that can be repeated 20,000 or more times, a molecular mass >8 million Da, and a length >20 μm. However, it has a very complex biology. It is a major, ubiquitous component of extracellular matrices involved in everything from fertilization, development, inflammations, to cancer. This JBC Review highlights some of these processes that were initiated through publications in the Journal of Biological Chemistry.Transforming growth factor β1 (TGFβ1) regulates CD44V6 expression and activity through extracellular signal-regulated kinase (ERK)-induced EGR1 in pulmonary fibrogenic fibroblasts
The appearance of myofibroblasts is generally thought to be the underlying cause of the fibrotic changes that underlie idiopathic pulmonary fibrosis. However, the cellular/molecular mechanisms that account for the fibroblast-myofibroblast differentiation/activation in idiopathic pulmonary fibrosis remain poorly understood. We investigated the functional role of hyaluronan receptor CD44V6 (CD44 containing variable exon 6 (v6)) for differentiation of lung fibroblast to myofibroblast phenotype. Increased hyaluronan synthesis and CD44 expression have been detected in numerous fibrotic organs.Transforming growth factor β1 (TGFβ1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain fibrosis and the myofibroblast phenotype has prevented the development of targeted therapies for IPF. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44V6 (CD44 variant containing exon 6), which enhances the TGFβ1 autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts.Tumor Necrosis Factor-stimulated Gene-6 (TSG-6) Is Constitutively Expressed in Adult Central Nervous System (CNS) and Associated with Astrocyte-mediated Glial Scar Formation following Spinal Cord Injury
Tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) binds to hyaluronan and can reorganize/stabilize its structure, also enhancing the binding of this glycosaminoglycan to its cell surface receptor, CD44. TSG-6 is rapidly up-regulated in response to inflammatory cytokines protecting tissues from the damaging effects of inflammation. Despite TSG-6 treatment having been shown to improve outcomes in an experimental model of traumatic brain injury, TSG-6 expression has not been extensively studied in the central nervous system (CNS).The Responses of Hyperglycemic Dividing Mesangial Cells to Heparin Are Mediated by the Non-reducing Terminal Trisaccharide
Background: Heparin prevents intracellular hyaluronan synthesis and subsequent autophagy in hyperglycemic dividing mesangial cells.Results: The non-reducing terminal trisaccharide of heparin is sufficient for this response.Conclusion: This heparin trisaccharide motif is exposed by the mammalian heparanase and is recognized by a receptor on dividing cells.Significance: The trisaccharide does not have the anti-coagulant properties of heparin.Hyaluronan and Its Heavy Chain Modification in Asthma Severity and Experimental Asthma Exacerbation
Background: Hyaluronan has been linked to asthma severity and inflammation.Results: We characterized the hyaluronan levels and its heavy chain modification in an experimental model of human asthma exacerbation.Conclusion: These data implicate hyaluronan and its heavy chain modification in human asthma severity.Significance: Repetitive asthma exacerbations exacerbate hyaluronan pathobiology, which contribute to the chronic inflammation associated with this disease.Heavy Chain Transfer by Tumor Necrosis Factor-stimulated Gene 6 to the Bikunin Proteoglycan
Background: The glycosaminoglycan of bikunin is less than 40 monosaccharides in length, but it can reversibly accept two heavy chains (HCs).Results: TSG-6 can reversibly transfer a single HC to the glycosaminoglycan of bikunin.Conclusion: The core protein, or sulfated glycosaminoglycan, of bikunin promotes reversible HC transfer to its relatively short CS chain.Significance: The intracellular assembly of inter-α-inhibitor is likely independent of transesterification by TSG-6.
