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
Related in: MedlinePlus
Mentions: To determine if Aiolos and Cereblon physically interact, co-immunoprecipitation experiments were performed in HEK-293T cells overexpressing Flag-CRBN and HA-Aiolos (Fig 3A). After immunoprecipitation with anti-Flag antibody, Aiolos protein was co-precipitated, but only in the presence of pomalidomide. Furthermore, overexpression of a mutant CRBN (YW/AA), which can no longer bind to the pomalidomide structural analogue thalidomide (Ito et al, 2010) abrogated the CRL4CRBN co-precipitation with Aiolos. Fig 3B shows that binding of Ikaros to Cereblon similarly occurred in a pomalidomide-dependent manner, with enhanced recovery of Ikaros. Taken together, drug binding promotes Cereblon engagement in interactions with the transcription factors Aiolos and Ikaros, proteins that are not readily detected as substrates in the absence of drug. These interactions lead to their degradation in T cells.