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Significance The identification of the Lon protease Cereblon as the thalidomide receptor has led to significant progress in our understanding of immunomodulatory drugs (IMiDs). IMiD binding alters the surface of Cereblon to facilitate the recruitment of proteins including Ikaros and CK1α. The recruitment of these proteins results in their ubiquitin-mediated proteosomal degradation. How Cereblon mediates the efficacy of these compounds in the treatment of inflammatory skin conditions remains unclear. Significantly, this study has identified Rabex-5 as a Cereblon-interacting protein that is affected by IMiD binding. Furthermore, knockdown studies in a human macrophage cell line reveals a function of Rabex-5 in regulating Toll-like receptor–induced type 1 IFN production. These findings may help explain the antiinflammatory properties of IMiDs.

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production