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CRBN
Cereblon

CRBN
Cereblon

Overview

Cereblon (CRBN) is a 442-amino acid protein located in the cytoplasm, nucleus, and peripheral membrane of neurologic tissue, as well as some others. CRBN helps regulate ion transport, modulates the AMP-activated protein kinase (AMPK) signaling pathway, and aids in metabolism in cells and whole tissues or organs. CRBN also has an effect in cell proliferation and apoptosis.1

CRBN is the target protein receptor of cullin ring ligase 4 cereblon (CRL4CRBN) E3 ubiquitin ligase complex, of which Ikaros and Aiolos are substrates.2 Encoded by the genes IKZF1 and IKZF3, respectively. Ikaros and Aiolos are members of the Ikaros family of zinc-finger transcription factors and are key to lymphocyte differentiation and B-cell development.2,3

  • Aiolos is required for the generation of high affinity bone marrow plasma cells,4 and Ikaros is a crucial differentiation factor for plasmacytoid dendritic cells.3
  • Genome-wide association studies have shown that polymorphisms in IKZF1 and IKZF3 correlated with an increased risk for developing systemic lupus erythematosus (SLE), and Ikaros and Aiolos were overexpressed in the peripheral blood of patients with SLE as compared to healthy controls.3,5
Cereblon Pathway

References

  1. Shi Q, Chen L. Cereblon: A Protein Crucial to the Multiple Functions of Immunomodulatory Drugs as well as Cell Metabolism and Disease Generation. J Immunol Res. 2017;2017:9130608.
  2. Gandhi AK, Kang J, Havens CG, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E 3 ubiquitin ligase complex CRL4 CRBN. Br J Haematol. 2014;164:811-821.
  3. Cytlak U, Resteu A, Bogaert D, et al. Ikaros family zinc finger 1 regulates dendritic cell development and function in humans. Nat Commun. 2018;9(1):1239.
  4. Cort├ęs M, Georgopoulos K. Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. J Exp Med. 2004;199(2):209-219.
  5. Schafer PH, Ye Y, Wu L, et al. Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus. Ann Rheum Dis. 2018;77(10):1516-1523.