Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production
| Autor: | Tadamitsu Kishimoto, David Millrine, Yohannes Gemechu, Mami Tei |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Ubiquitin-Protein Ligases Plasma protein binding Biology 03 medical and health sciences medicine Guanine Nucleotide Exchange Factors Humans Immunologic Factors STAT1 Receptor Lenalidomide Adaptor Proteins Signal Transducing Immunity Cellular Multidisciplinary Binding Sites Cereblon Toll-Like Receptors Biological Sciences Cell biology Thalidomide 030104 developmental biology Cytokine Proteasome Gene Knockdown Techniques Multiprotein Complexes Immunology Interferon Type I biology.protein Guanine nucleotide exchange factor Interferon type I medicine.drug Peptide Hydrolases Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 113(38) |
| ISSN: | 1091-6490 |
| Popis: | Immunomodulatory drugs (IMiDs) are a family of compounds derived from thalidomide. Binding of the IMiD molecule to the Lon protease Cereblon initiates the degradation of substrates via the ubiquitin proteasome pathway. Here, we show that Cereblon forms a complex with Rabex-5, a regulator of immune homeostasis. Treatment with lenalidomide prevented the association of Cereblon with Rabex-5. Conversely, mutation of the IMiD binding site increased Cereblon-Rabex-5 coimmunoprecipitation. The thalidomide binding region of Cereblon therefore regulates the formation of this complex. Knockdown of Rabex-5 in the THP-1 macrophage cell line up-regulated Toll-like receptor (TLR)-induced cytokine and type 1 IFN production via a STAT1/IRF activating pathway. Thus, we identify Rabex-5 as a IMiD target molecule that functions to restrain TLR activated auto-immune promoting pathways. We propose that release of Rabex-5 from complex with Cereblon enables the suppression of immune responses, contributing to the antiinflammatory properties of IMiDs. |
| Databáze: | OpenAIRE |
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