Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production.
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.
Laboratory of Immune Regulation, World Premier Immunology Frontier Research Centre, Osaka University, Osaka 565-0871, Japan.
David
D
Millrine
Laboratory of Immune Regulation, World Premier Immunology Frontier Research Centre, Osaka University, Osaka 565-0871, Japan.
Mami
M
Tei
Laboratory of Immune Regulation, World Premier Immunology Frontier Research Centre, Osaka University, Osaka 565-0871, Japan.
Yohannes
Y
Gemechu
Laboratory of Immune Regulation, World Premier Immunology Frontier Research Centre, Osaka University, Osaka 565-0871, Japan kishimoto@ifrec.osaka-u.ac.jp.
Tadamitsu
T
Kishimoto
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics*; D007155:Immunologic Factors / Q000494:pharmacology; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics*; D000077269:Lenalidomide; D046912:Multiprotein Complexes / Q000187:drug effects / Q000235:genetics; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D020662:Guanine Nucleotide Exchange Factors; D007155:Immunologic Factors; D007370:Interferon Type I; D046912:Multiprotein Complexes; C108382:RABGEF1 protein, human; D051193:Toll-Like Receptors; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide
Cereblon; IMiD; STAT1; TLR; interferon