Advanced-glycation-end-product-induced formation of immunoproteasomes: involvement of RAGE and Jak2/STAT1.
AGEs (advanced glycation-end products) accumulate during aging and several pathologies such as Alzheimer's disease and diabetes. These protein products are known to inhibit proteolytic pathways. Moreover, AGEs are known to be involved in the activation of immune responses. In the present study we demonstrate that AGEs induce the expression of immunoproteasomal subunits. To elucidate a molecular basis underlying the observed effects we were able to demonstrate an activation of the Jak2 (Janus kinase 2)/STAT1 (signal transducer and activator of transcription 1) pathway. Inhibition of Jak2 by AG-490 and STAT1 by specific siRNA (small interfering RNA) abolished AGE-induced expression of immunoproteasomal subunits. Furthermore, silencing of RAGE (receptor for AGEs) revealed that AGE-induced up-regulation of the immunoproteasome is mediated by a RAGE signalling process. Thus we have described for the first time that the signalling pathway of Jak2 and STAT1 activated by AGEs via RAGE is involved in the induction of the immunoproteasome.
Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany.
Stefanie
S
Grimm
Christiane
C
Ott
Melanie
M
Hörlacher
Daniela
D
Weber
Annika
A
Höhn
Tilman
T
Grune
D000818:Animals; D045744:Cell Line, Tumor / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D007371:Interferon-gamma / Q000502:physiology; D053614:Janus Kinase 2 / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000502:physiology*; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D020032:Tyrphostins; C081628:advanced glycation end products-bovine serum albumin; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C071313:LMP-2 protein; D012710:Serum Albumin, Bovine; D007371:Interferon-gamma; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; C098948:PSMB10 protein, human; D046988:Proteasome Endopeptidase Complex; C486213:Psme1 protein, mouse