RAGE (receptor) explained

RAGE (receptor for advanced glycation endproducts), also called AGER, is a 35 kilodalton transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper et al.[1] Its name comes from its ability to bind advanced glycation endproducts (AGE), which include chiefly glycoproteins, the glycans of which have been modified non-enzymatically through the Maillard reaction. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common structural motif, RAGE is often referred to as a pattern recognition receptor. RAGE also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively, and by active secretion from macrophages, natural killer cells, and dendritic cells.

The interaction between RAGE and its ligands is thought to result in pro-inflammatory gene activation.[2] [3] Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors.

Isoforms of the RAGE protein, which lack the transmembrane and the signaling domain (commonly referred to as soluble RAGE or sRAGE) are hypothesized to counteract the detrimental action of the full-length receptor and are hoped to provide a means to develop a cure against RAGE-associated diseases.

Gene and polymorphisms

The RAGE gene lies within the major histocompatibility complex (MHC class III region) on chromosome 6 and comprises 11 exons interlaced by 10 introns. Total length of the gene is about 1400 base pairs (bp) including the promoter region, which partly overlaps with the PBX2 gene.[4] About 30 polymorphisms are known most of which are single-nucleotide polymorphisms.[5]

RNA and alternative splicing

The primary transcript of the human RAGE gene (pre-mRNA) is thought to be alternatively spliced. So far about 6 isoforms including the full length transmembrane receptor have been found in different tissues such as lung, kidney, brain etc. Five of these 6 isoforms lack the transmembrane domain and are thus believed to be secreted from cells. Generally these isoforms are referred to as sRAGE (soluble RAGE) or esRAGE (endogenous secretory RAGE). One of the isoforms lacks the V-domain and is thus believed not to be able to bind RAGE ligands.

Structure

RAGE exists in the body in two forms: a membrane-bound form known as mRAGE, and a soluble form, known as sRAGE. mRAGE has three domains, and sRAGE has only the extracellular domain. sRAGE is either the product of alternative splicing or the product of proteolytic cleavage of mRAGE.[6]

The full receptor consists of the following domains: The cytosolic domain, which is responsible for signal transduction, the transmembrane domain which anchors the receptor in the cell membrane, the variable domain which binds the RAGE ligands, and two constant domains.

Ligands

RAGE is able to bind several ligands and therefore is referred to as a pattern-recognition receptor. Ligands which have so far been found to bind RAGE are:

RAGE and disease

RAGE has been linked to several chronic diseases, which are thought to result from vascular damage. The pathogenesis is hypothesized to include ligand binding, upon which RAGE signals activation of nuclear factor kappa B (NF-κB). NF-κB controls several genes involved in inflammation. RAGE itself is upregulated by NF-κB. Given a condition in which there is a large amount of a RAGE ligand present (e.g. AGE in diabetes or amyloid-β-protein in Alzheimer's disease) this establishes a positive feed-back cycle, which leads to chronic inflammation. This chronic condition is then believed to alter the micro- and macrovasculature, resulting in organ damage or even organ failure.[12] However, whilst RAGE is up-regulated in inflammatory conditions, it is down-regulated in lung cancer and pulmonary fibrosis.[6] Diseases that have been linked to RAGE are:

RAGE is expressed at the highest levels in the lung compared to other tissues, in particular in alveolar type I cells, and is lost in idiopathic pulmonary fibrosis (IPF) indicating that expression and regulation of RAGE in the pulmonary system differs from that in the vascular system. Blockade/knockdown of RAGE resulted in impaired cell adhesion, and increased cell proliferation and migration[18]

Inhibitors

A number of small molecule RAGE inhibitors or antagonists have been reported.[19] [20] [21] [22]

Azeliragon: vTv Therapeutics (formerly TransTech Pharma) sponsored a Phase 3 clinical trial of their RAGE inhibitor Azeliragon (TTP488) for mild Alzheimer's disease.[23] These trials were halted in 2018.[24]

AGE receptors

Besides RAGE there are other receptors which are believed to bind advanced glycation endproducts. However, these receptors could play a role in the removal of AGE rather than in signal transduction as is the case for RAGE. Other AGE receptors are:

Further reading

External links

Notes and References

  1. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A . Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins . The Journal of Biological Chemistry . 267 . 21 . 14998–5004 . July 1992 . 10.1016/S0021-9258(18)42138-2 . 1378843 . free .
  2. Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Klöting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Häring HU, Schleicher E, Nawroth PP . Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB . Diabetes . 50 . 12 . 2792–808 . December 2001 . 11723063 . 10.2337/diabetes.50.12.2792 . free .
  3. Gasparotto . J . Girardi . CS . Somensi . N . Ribeiro . CT . Moreira . JCF . Michels . M . Sonai . B . Rocha . M . Steckert . AV . Barichello . T . Quevedo . J . Dal-Pizzol . F . Gelain . DP . Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment . J Biol Chem . Nov 2017 . 293 . 1 . 226–244 . 10.1074/jbc.M117.786756 . 29127203 . 5766916 . free .
  4. Hudson BI, Stickland MH, Futers TS, Grant PJ . Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy . Diabetes . 50 . 6 . 1505–11 . June 2001 . 11375354 . 10.2337/diabetes.50.6.1505 . free .
  5. Hudson BI, Hofman MA, Bucciarelli L, Wendt T, Moser B, Lu Y, Qu W, Stern DM, D'Agati V, Yan SD, Yan SF, Grant PJ . Glycation and diabetes: The RAGE connection . Current Science . 83 . 12 . 2002 . 1515–1521 .
  6. Oczypok . EA . Perkins . TN . Oury . TD . All the "RAGE" in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses. . Paediatric Respiratory Reviews . June 2017 . 23 . 40–49 . 10.1016/j.prrv.2017.03.012 . 28416135. 5509466 .
  7. Ibrahim ZA, Armour CL, Phipps S, Sukkar MB . RAGE and TLRs: relatives, friends or neighbours? . Molecular Immunology . 56 . 4 . 739–44 . December 2013 . 23954397 . 10.1016/j.molimm.2013.07.008 .
  8. Penumutchu SR, Chou RH, Yu C . Structural insights into calcium-bound S100P and the V domain of the RAGE complex . PLOS ONE . 9 . 8 . e103947 . 2014 . 25084534 . 4118983 . 10.1371/journal.pone.0103947 . 2014PLoSO...9j3947P . free .
  9. Penumutchu SR, Chou RH, Yu C . Interaction between S100P and the anti-allergy drug cromolyn . Biochemical and Biophysical Research Communications . 454 . 3 . 404–9 . November 2014 . 25450399 . 10.1016/j.bbrc.2014.10.048 .
  10. Hermani A, De Servi B, Medunjanin S, Tessier PA, Mayer D . S100A8 and S100A9 activate MAP kinase and NF-kappaB signaling pathways and trigger translocation of RAGE in human prostate cancer cells . Experimental Cell Research . 312 . 2 . 184–97 . January 2006 . 16297907 . 10.1016/j.yexcr.2005.10.013 .
  11. Dahlmann M, Okhrimenko A, Marcinkowski P, Osterland M, Herrmann P, Smith J, Heizmann CW, Schlag PM, Stein U . RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis . Oncotarget . 5 . 10 . 3220–33 . May 2014 . 24952599 . 4102805 . 10.18632/oncotarget.1908 .
  12. Gasparotto . J . Ribeiro . CT . da Rosa-Silva . HT . Bortolin . RC . Rabelo . TK . Peixoto . DO . Moreira . JCF . Gelain . DP . Systemic Inflammation Changes the Site of RAGE Expression from Endothelial Cells to Neurons in Different Brain Areas . Mol Neurobiol . May 2019 . 56 . 5 . 3079–3089 . 10.1007/s12035-018-1291-6 . 30094805 . 11323/1858 . 51953478 . free .
  13. Yammani RR . S100 proteins in cartilage: role in arthritis . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1822 . 4 . 600–6 . April 2012 . 22266138 . 10.1016/j.bbadis.2012.01.006 . 3294013.
  14. Kipfmueller . Florian . Expression of soluble receptor for advanced glycation end products is associated with disease severity in congenital diaphragmatic hernia . Am J Physiol Lung Cell Mol Physiol . 6 March 2019 . 316 . 6 . L1061–L1069 . 10.1152/ajplung.00359.2018 . 30838867 . free .
  15. Kuroiwa Y, Takakusagi Y, Kusayanagi T, Kuramochi K, Imai T, Hirayama T, Ito I, Yoshida M, Sakaguchi K, Sugawara F . Identification and characterization of the direct interaction between methotrexate (MTX) and high-mobility group box 1 (HMGB1) protein . PLOS ONE . 8 . 5 . e63073 . May 2013 . 23658798 . 10.1371/journal.pone.0063073 . 3643934. 2013PLoSO...863073K . free .
  16. Mahajan N, Mahmood S, Jain S, Dhawan V . Receptor for advanced glycation end products (RAGE), inflammatory ligand EN-RAGE and soluble RAGE (sRAGE) in subjects with Takayasu's arteritis . International Journal of Cardiology . 168 . 1 . 532–4 . September 2013 . 23398829 . 10.1016/j.ijcard.2013.01.002 .
  17. Dwir . Daniella . Giangreco . Basilio . Xin . Lijing . Tenenbaum . Liliane . Cabungcal . Jan-Harry . Steullet . Pascal . Goupil . Audrey . Cleusix . Martine . Jenni . Raoul . Chtarto . Abdelwahed . Baumann . Philipp S. . Klauser . Paul . Conus . Philippe . Tirouvanziam . Rabindra . Cuenod . Michel . November 2020 . MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients . Molecular Psychiatry . en . 25 . 11 . 2889–2904 . 10.1038/s41380-019-0393-5 . 30911107 . 7577857 . 1476-5578. 11343/252888 . free .
  18. Queisser MA, Kouri FM, Königshoff M, Wygrecka M, Schubert U, Eickelberg O, Preissner KT . Loss of RAGE in pulmonary fibrosis: molecular relations to functional changes in pulmonary cell types . American Journal of Respiratory Cell and Molecular Biology . 39 . 3 . 337–45 . September 2008 . 18421017 . 10.1165/rcmb.2007-0244OC .
  19. Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ, Thiyagarajan M, Zarcone T, Fritz G, Friedman AE, Miller BL, Zlokovic BV . A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease . The Journal of Clinical Investigation . 122 . 4 . 1377–92 . April 2012 . 22406537 . 3314449 . 10.1172/JCI58642 .
  20. Han YT, Choi GI, Son D, Kim NJ, Yun H, Lee S, Chang DJ, Hong HS, Kim H, Ha HJ, Kim YH, Park HJ, Lee J, Suh YG . Ligand-based design, synthesis, and biological evaluation of 2-aminopyrimidines, a novel series of receptor for advanced glycation end products (RAGE) inhibitors . Journal of Medicinal Chemistry . 55 . 21 . 9120–35 . November 2012 . 22742537 . 10.1021/jm300172z .
  21. Han YT, Kim K, Choi GI, An H, Son D, Kim H, Ha HJ, Son JH, Chung SJ, Park HJ, Lee J, Suh YG . Pyrazole-5-carboxamides, novel inhibitors of receptor for advanced glycation end products (RAGE) . European Journal of Medicinal Chemistry . 79 . 128–42 . May 2014 . 24727489 . 10.1016/j.ejmech.2014.03.072 .
  22. Han YT, Kim K, Son D, An H, Kim H, Lee J, Park HJ, Lee J, Suh YG . Fine tuning of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine focusing on the activity-sensitive aminoalkoxy moiety for a therapeutically useful inhibitor of receptor for advanced glycation end products (RAGE) . Bioorganic & Medicinal Chemistry . 23 . 3 . 579–87 . February 2015 . 25533401 . 10.1016/j.bmc.2014.12.003 .
  23. Web site: Azeliragon. vTv Therapeutics. 23 July 2015.
  24. https://www.genengnews.com/gen-news-highlights/vtv-halts-trials-of-alzheimer-s-candidate-azeliragon-after-phase-iii-failure/81255684/ vTv Halts Trials of Alzheimer's Candidate Azeliragon after Phase III Failure Apr 2018

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