Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.).
Bottom Line: We confirm that Aiolos and Ikaros are transcriptional repressors of interleukin-2 expression.The findings link lenalidomide- or pomalidomide-induced degradation of these transcriptional suppressors to well documented T cell activation.In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4(CRBN) , leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.
Affiliation: Celgene Corporation, Summit, NJ, USA.Show MeSH
Mentions: The results described above suggest that lenalidomide or pomalidomide binding enables CRL4CRBN to associate with Ikaros and Aiolos, thus enabling their ubiquitination. To investigate whether drug-induced degradation of Aiolos and Ikaros in T cells occurs in a Cereblon-dependent manner, primary T cells were transfected with an siRNA against CRBN or control siRNA. CRBN siRNA resulted in a 75% decrease in CRBN mRNA levels compared with a non-targeting siRNA control (Fig 5A). Previous studies have established that a similar degree of knockdown leads to abrogation of lenalidomide- or pomalidomide-induced IL2 upregulation in T cells (Lopez-Girona et al, 2012). Figure5B demonstrates that the ability of lenalidomide or pomalidomide to induce Aiolos and Ikaros degradation in T cells was abrogated in the presence of CRBN siRNA, but not a non-targeting control siRNA. These data show that lenalidomide and pomalidomide induce degradation of Aiolos and Ikaros in a Cereblon-dependent manner.