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.).
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.).
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DOI：
10.1111/bjh.12708
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发表时间：
2014-03
影响因子：
6.5
通讯作者：
Chopra R
中科院分区：
文献类型：
--
作者：
Gandhi AK;Kang J;Havens CG;Conklin T;Ning Y;Wu L;Ito T;Ando H;Waldman MF;Thakurta A;Klippel A;Handa H;Daniel TO;Schafer PH;Chopra R
来那度胺和泊马度胺的分子靶标雷公藤多胺(Cereblon，CRBN)是扑杀素环E3泛素连接酶复合体CRL4CRBN的底物受体。来那度胺或泊马度胺对T细胞的共刺激是依赖于脑白素的：然而，负责T细胞共刺激的CRL4CRBN底物尚未确定。在这里，我们证明了转录因子Ikaros(由IKZF1基因编码)和Aiolos(由IKZF3基因编码的IKZF3)与CRL4CRBN的相互作用是由来那度胺或泊马度胺诱导的。每种药物都通过增强泛素化促进Aiolos和Ikaros与CRL4CRBN的结合，导致T淋巴细胞中依赖于小脑的蛋白酶体降解。我们证实Aiolos和Ikaros是IL-2表达的转录抑制因子。这些发现将来那度胺或泊马度胺诱导的这些转录抑制因子的降解与T细胞激活联系在一起。重要的是，Aiolos可以作为来那度胺和泊马度胺的近端药效学标志物，因为服用来那度胺的健康受试者显示出其外周T细胞中Aiolos的降解。总之，我们提出了一个分子模型，在该模型中，药物与Cereblon结合导致Ikaros和Aiolos与CRL4CRBN相互作用，导致它们泛素化，随后蛋白酶体降解和T细胞激活。
Cereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4CRBN. T cell co-stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL4CRBN substrates responsible for T cell co-stimulation have yet to be identified. Here we demonstrate that interaction of the transcription factors Ikaros (IKZF1, encoded by the IKZF1 gene) and Aiolos (IKZF3, encoded by the IKZF3 gene) with CRL4CRBN is induced by lenalidomide or pomalidomide. Each agent promotes Aiolos and Ikaros binding to CRL4CRBN with enhanced ubiquitination leading to cereblon-dependent proteosomal degradation in T lymphocytes. 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. Importantly, Aiolos could serve as a proximal pharmacodynamic marker for lenalidomide and pomalidomide, as healthy human subjects administered lenalidomide demonstrated Aiolos degradation in their peripheral T cells. In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4CRBN, leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
20.3
作者：
Ferreiros-Vidal, Isabel;Carroll, Thomas;Merkenschlager, Matthias
通讯作者：
Merkenschlager, Matthias
影响因子：
4.4
作者：
Thomas, Rajan M.;Chunder, Neelanjana;Wells, Andrew D.
通讯作者：
Wells, Andrew D.
影响因子：
11.4
作者：
Lopez-Girona, A.;Mendy, D.;Ito, T.;Miller, K.;Gandhi, A. K.;Kang, J.;Karasawa, S.;Carmel, G.;Jackson, P.;Abbasian, M.;Mahmoudi, A.;Cathers, B.;Rychak, E.;Gaidarova, S.;Chen, R.;Schafer, P. H.;Handa, H.;Daniel, T. O.;Evans, J. F.;Chopra, R.
通讯作者：
Chopra, R.
影响因子：
11.5
作者：
Wu, Lei;Adams, Mary;Bartlett, J. Blake
通讯作者：
Bartlett, J. Blake