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Single subunit degradation of WIZ, a lenalidomide- and pomalidomide dependent substrate of E3 ubiquitin ligase CRL4^(CRBN)

Yu, Helen H. and Reitsma, Justin M. and Sweredoski, Mike J. and Moradian, Annie and Hess, Sonja and Deshaies, Raymond J. (2019) Single subunit degradation of WIZ, a lenalidomide- and pomalidomide dependent substrate of E3 ubiquitin ligase CRL4^(CRBN). . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20190402-104546411

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Abstract

Immunomodulators (IMiDs) are an effective class of drugs used to treat blood cancers. IMiDs are believed to work by recruiting protein targets containing a β-hairpin motif for ubiquitination by E3 ubiquitin ligase complexes 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 repertoire of proteins that show an increased physical association with CRBN after IMiD treatment, we identified a novel IMiD substrate, Widely Interspaced Zinc Finger Motifs (WIZ). WIZ contains a C2H2 zinc finger domain, like several other substrates that were previously characterized. We demonstrate that IMiDs stabilize 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 IMiDs but 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 repertoire of proteins that are targeted for degradation by IMiD compounds will be required to better understand their biological effects.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/595389DOIDiscussion Paper
https://www.biorxiv.org/content/10.1101/595389v1OrganizationDiscussion Paper
ORCID:
AuthorORCID
Sweredoski, Mike J.0000-0003-0878-3831
Moradian, Annie0000-0002-0407-2031
Hess, Sonja0000-0002-5904-9816
Deshaies, Raymond J.0000-0002-3671-9354
Alternate Title:Single subunit degradation of WIZ, a lenalidomide- and pomalidomide dependent substrate of E3 ubiquitin ligase CRL4CRBN
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license. bioRxiv preprint first posted online Apr. 2, 2019. Thanks to Rati Verma, Jennifer Mamrosh, Emily Blythe, Thang Nguyen, and David Sherman for scientific discussion. Thanks to Thang Nguyen for MM.1s CRBN KD and parental cell lines, and preparing samples in Fig. 2. H.H.Y was supported by NSF GRFP fellowship. R.J.D. was an investigator at the Howard Hughes Medical institute, and this work was supported by HHMI and a gift from Amgen.
Funders:
Funding AgencyGrant Number
NSF Graduate Research FellowshipUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
AmgenUNSPECIFIED
Record Number:CaltechAUTHORS:20190402-104546411
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190402-104546411
Official Citation:Single subunit degradation of WIZ, a lenalidomide- and pomalidomide dependent substrate of E3 ubiquitin ligase CRL4CRBN. Helen H. Yu, Justin M. Reitsma, Mike J. Sweredoski, Annie Moradian, Sonja Hess, Raymond J. Deshaies. bioRxiv 595389; doi: https://doi.org/10.1101/595389
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94364
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:02 Apr 2019 18:14
Last Modified:03 Oct 2019 21:03

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