Single subunit degradation of WIZ, a lenalidomide- and pomalidomide dependent substrate of E3 ubiquitin ligase CRL4CRBN

Immunomodulators ( IMiDs) are an effective class of drugs used to treat blood cancers. IMiDsare believed to work by recruiting protein targetscontaining a β-hairpin motif for ubiquitination by E3 ubiquitin ligasecomplexes composed of cereblon(CRBN), Cullin-4a ( CUL4a), DNA Damage Binding protein-1 ( DDB1), and Ring Box-1 ( RBX1). The ubiquitinated protein is subsequently degraded by the proteasome. By characterizing the repertoireof proteins that show an increased physical association with CRBN after IMiDtreatment, we identified a novel IMiDsubstrate, Widely Interspaced Zinc FingerMotifs (WIZ). WIZ contains a C2H2 zinc fingerdomain, like several other substrates that were previously characterized. We demonstrate that IMiDsstabilize physical association of WIZ with CRBN, deplete WIZ steady state protein levels in a way that is dependent on E3 ligase activity, and enhance the rate of its degradation. Notably, proteins that assemble with WIZ are co-recruited to CRBN by IMiDsbut are not degraded, illustrating the potential of targeted protein degradation to eliminate individual subunits of a protein complex. These findings suggest that systematic characterization of the full repertoireof proteins that are targeted for degradation by IMiDcompounds will be required to better understand their biological effects.