Advanced-glycation-end-product-induced formation of immunoproteasomes: involvement of RAGE and Jak2/STAT1
Abstract
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 AGEinduced 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.
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Upon binding to their cognate receptor, AGEs trigger activation of downstream effectors including ERK1/2, p38 MAPK, rho-GTPases, JAK, JNK, and NF-kB.
“Upon binding to their cognate receptor, AGEs trigger the activation of different downstream effectors, including extracellularsignal-regulated kinase 1/2 and p38 mitogen-activated protein kinase, rho-GTPases, Janus kinase, c-Jun N-terminal kinase (JNK), and the transcription factor nuclear-factor-kappa B (NF-𝜅B).[49][50][51][52][53]”
From The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction (2021) · cites this paper as [49]
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Self-citation
- Authors
- Grimm, S., Ott, C., Hörlacher, M., Weber, D., Höhn, A., & Grune, T.
- Affiliations
- University of Hohenheim (DE)
- Friedrich Schiller University Jena (DE)
- Corresponding author
- Grimm, Stefanie
- Ott, Christiane
- Weber, Daniela
- Grune, Tilman
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2012-10-18
- Volume
- 448
- Issue
- 1
- Pages
- 127-139
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W1979388970
- Cited by
- 87
- References
- 48
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 7 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 13 · 2019: 11 · 2018: 6 · 2017: 3 · 2016: 8 · 2015: 6 · 2014: 11 · 2013: 5
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- advanced glycation end products, immunoproteasome, RAGE, JAK2/STAT1 signaling, AG490, Alzheimer's disease, diabetes mellitus
- MeSH terms
- Receptor for Advanced Glycation End Products, Animals, Cysteine Endopeptidases, Gene Expression Regulation, Interferon-gamma, Macrophages, Phosphorylation, Protein Processing, Post-Translational, Receptors, Immunologic, RNA, Messenger, Serum Albumin, Bovine, Transcription, Genetic, Signal Transduction, Glycation End Products, Advanced, Tyrphostins, RNA, Small Interfering, Cell Line, Tumor, Proteasome Endopeptidase Complex, STAT1 Transcription Factor, Mice, Janus Kinase 2
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