131: Pomalidomide disrupts the association between Cereblon and Rabex-5 resulting in the suppression of TLR induced cytokine production

Abstract

The Teratogenic properties of Thalidomide, in addition to its efficacy in the treatment of Multiple Myeloma, are dependent on Cereblon. Importantly however, the role of Cereblon in mediating Thalidomide’s anti-inflammatory properties remains unclear. Using shRNA knockdown we show that Cereblon functions critically in TLR induced signal transduction. Furthermore, we show that under physiological conditions a proportion of total cellular Cereblon exists in complex with Rabex-5, a mediator of endosomal transport. This interaction was found to be dependent on the Rabex-5N terminal ubiquitin binding domain. Significantly, the Thalidomide derivative Pomalidomide was shown to reduce the association of Cereblon with Rabex-5. We further show that Pomalidomide inhibits TRIF/IRF3 dependent gene induction and that both Cereblon and Rabex-5 function critically in this pathway. These findings clearly indicate that the anti-inflammatory properties of Thalidomide derivatives result from interference with the function of Cereblon and Rabex-5 in TLR induced signal transduction. We anticipate that further investigation of the relationship between Cereblon and Rabex-5 will inform our understanding of Thalidomide and its derivatives in other contexts. Moreover, the identification of Cereblon as a critical regulator of the TLR signalling apparatus will reveal novel aspects of signal transduction and contribute to our understanding of innate immunity.