Mouse Specific Cleavage-Resistant RAGE Splice Variant.

Tohru Fukai

doi:10.1371/journal.pone.0162120

Abstract

Receptor for Advanced Glycation Endproducts (RAGE), a transmembrane, multi-ligand, pattern recognition receptor, has been implicated in a range of inflammatory disease including diabetes, cancers, and cardiovascular disease (CVD) [1]. In addition to the full length receptor, soluble form of RAGE (sRAGE) has been shown to prevent the development of numerous pathologic states, and therefore highlights RAGE as an attractive therapeutic target [2–7]. sRAGE lacks the trans-membrane domain and is secreted to the extracellular milieu [6]. RAGE and sRAGE share the entire extracellular portion encompassing the V, C1 and C2 immunoglobulin-like domains (Fig 1). This feature renders sRAGE to function as a decoy that binds ligands and reduces the inflammatory signaling capacity of its membrane-bound counterpart [5, 7]. The importance of sRAGE is underscored by clinical cohort studies showing that serum sRAGE levels are correlated with clinical disease states including CVD, diabetes, cancer and various inflammatory disease states [6, 8].

Highlights

Endogenous soluble form of RAGE (sRAGE) isoforms have been identified in human and mouse serum which are generated through two distinct biological mechanisms (Fig 1)
Ectodomain shedding of cell surface receptors can affect a number of processes such as the loss of cell-cell or cell-matrix interactions, the productions of a soluble ectodomain that acts as a agonist/antagonist for the cell surface protein and the release of the intercellular domain (ICD) of the receptor to induce cell signaling [13, 14]
Lin and colleagues showed that after serum starvation, the majority of mRAGE-FL is localized at the lysosome, whereas mRAGEv4, in stark contrast, remains localized at the plasma membrane. This finding suggests that the 9-residue structural element which lacks in mRAGEv4 is required for cleavage of mRAGE-FL by sheddases, and for the intracellular cellular trafficking of the full-length receptor

Summary

Introduction

Endogenous sRAGE isoforms have been identified in human and mouse serum which are generated through two distinct biological mechanisms (Fig 1). The alternative splicing of the transmembrane region of RAGE leading to a secreted isoform (endogenous sRAGE (esRAGE)) in both humans (variant 1 isoform) and mice (variant 1 and 3 isoforms).

Results

Conclusion