Heparan Sulfate Is Essential for High Mobility Group Protein 1 (HMGB1) Signaling by the Receptor for Advanced Glycation End Products (RAGE)

Abstract

Background:The cytokine function of the danger-associated molecular pattern protein HMGB1 is mediated through RAGE. Results: HMGB1-RAGE signaling depends on heparan sulfate, but heparan sulfate binding to HMGB1 is dispensable. Conclusion: Heparan sulfate is essential for HMGB1 signaling because RAGE binds heparan sulfate. Significance: Perturbing heparan sulfate may be a novel strategy to alter RAGE-dependent signaling.

Receptor for Advanced Glycation End Products (RAGE) Functions as Receptor for Specific Sulfated Glycosaminoglycans, and Anti-RAGE Antibody or Sulfated Glycosaminoglycans Delivered in Vivo Inhibit Pulmonary Metastasis of Tumor Cells

“…Most recently, Rao et al (36) reported that low anticoagulant heparin binds to RAGE and inhibits its interaction with ligands such as high mobility group box protein-1 and S100 calgranulins and that the inhibition of this binding leads to anti-inflammatory effects on leukocyte-mediated inflammation. Furthermore, Xu et al (47) showed that HS was involved in the signaling of HMGB1 through RAGE. The interactions of RAGE with GAGs including CS-E and heparin are consistent with these observations and may primarily depend on their sulfation pattern, electrostatic potential, and conformation.…”

Novel insights for high mobility group box 1 protein-mediated cellular immune response in sepsis:A systemic review

“…[42] As a receptor of multiple ligands, RAGE has been implicated as a critical receptor mediating the cytokine activity of HMGB1 in Tregs and macrophages. [25,43] Interaction of RAGE with ligand has two main consequences: one is to activate CDC42, Rac, and guanosine triphosphatases that regulate cell motility, and the other pathway activates several MAPKs and subsequently leads to activation of nuclear factor (NF)-κB. [44] Interaction of RAGE and HMGB1 causes phosphorylation of MAPKs (e.g., p38 and p42/44 kinases, stress-activated protein kinase/c-Jun N-terminal kinase, ERK1/2) and activation of the NF-κB signaling pathway in cultured macrophages, neutrophils, and Caco-2 epithelial cells.…”

An improved expression system for the VC1 ligand binding domain of the receptor for advanced glycation end products in Pichia pastoris

“…It contributes to the inflammatory 59 response [2] and participates to innate and adaptive immunity, 60 where the activation of human RAGE (hRAGE) leads to the produc- that is involved in cell growth and migration, and finally (iv) the 76 NADPH oxidase pathway that leads to ROS formation [ wide spectrum of ligands [8], the majority of which are: AGEs, 96 i.e., products generated by the non-enzymatic glycation and subse-97 quent oxidation of proteins, amyloid-b-peptides, b-sheet fibrils and 98 members of the S100/calgranulin protein family [9]. Additional cule [6], the lipopolysaccharide of bacterial walls (LPS), the com-104 plement component C1q [10], chondroitin sulfate and heparan 105 sulfate [11,12] and nucleic acids [13]. hRAGE ligands do not share 106 sequence or structural similarity but all display a negatively 107 charged surface at neutral pH and many ligands show the tendency 108 to oligomerize [14].…”