UBE2G1 governs the destruction of cereblon neomorphic substrates
- Celgene, United States
Abstract
The cereblon modulating agents (CMs) including lenalidomide, pomalidomide and CC-220 repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the K48-linked polyubiquitination of CRL4CRBN neomorphic substrates via a sequential ubiquitination mechanism. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent IKZF1/3 degrader CC-220. Collectively, it will be of fundamental interest to explore if loss of UBE2G1 activity is linked to clinical resistance to drugs that hijack the CRL4CRBN to eliminate disease-driving proteins.
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All data generated or analysed during this study are included in the manuscript and supporting files
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Funding
No external funding was received for this work
Reviewing Editor
- Wade Harper, Harvard Medical School, United States
Version history
- Received: August 10, 2018
- Accepted: September 19, 2018
- Accepted Manuscript published: September 20, 2018 (version 1)
- Version of Record published: October 12, 2018 (version 2)
Copyright
© 2018, Lu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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UBE2G1 governs the destruction of cereblon neomorphic substrates
eLife 7:e40958.
https://doi.org/10.7554/eLife.40958
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