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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Gang Lu

    PH TCoE, Celgene, San Diego, United States
    For correspondence
    glu@celgene.com
    Competing interests
    Gang Lu, Employee of Celgene.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2138-1522
  2. Stephanie Weng

    PH TCoE, Celgene, San Diego, United States
    Competing interests
    Stephanie Weng, Employee of Celgene.
  3. Mary Matyskiela

    Structral and Chemical Biology, Celgene, San Diego, United States
    Competing interests
    Mary Matyskiela, Employee of Celgene.
  4. Xinde Zheng

    PH TCoE, Celgene, San Diego, United States
    Competing interests
    Xinde Zheng, Employee of Celgene.
  5. Wei Fang

    Structral and Chemical Biology, Celgene, San Diego, United States
    Competing interests
    Wei Fang, Employee of Celgene.
  6. Scott Wood

    PH TCoE, Celgene, San Diego, United States
    Competing interests
    Scott Wood, Employee of Celgene.
  7. Christine Surka

    PH TCoE, Celgene, San Diego, United States
    Competing interests
    Christine Surka, Employee of Celgene.
  8. Reina Mizukoshi

    PH TCoE, Celgene, San Diego, United States
    Competing interests
    Reina Mizukoshi, Employee of Celgene.
  9. Chin-Chun Lu

    PH TCoE, Celgene, San Diego, United States
    Competing interests
    Chin-Chun Lu, Employee of Celgene.
  10. Derek Mendy

    PH TCoE, Celgene, San Diego, United States
    Competing interests
    Derek Mendy, Employee of Celgene.
  11. In Sock Jang

    Research Analytics, Celgene, San Diego, United States
    Competing interests
    In Sock Jang, Employee of Celgene.
  12. Kai Wang

    Research Analytics, Celgene, San Diego, United States
    Competing interests
    Kai Wang, Employee of Celgene.
  13. Mathieu Marella

    NCD - Exploratory Toxicology, Celgene, San Diego, United States
    Competing interests
    Mathieu Marella, Employee of Celgene.
  14. Suzana Couto

    NCD - Exploratory Toxicology, Celgene, San Diego, United States
    Competing interests
    Suzana Couto, Employee of Celgene.
  15. Brian Cathers

    PH TCoE, Celgene, San Diego, United States
    Competing interests
    Brian Cathers, Employee of Celgene.
  16. James Carmichael

    PH TCoE, Celgene, San Diego, United States
    Competing interests
    James Carmichael, Employee of Celgene.
  17. Philip Chamberlain

    Structral and Chemical Biology, Celgene, San Diego, United States
    Competing interests
    Philip Chamberlain, Employee of Celgene.
  18. Mark Rolfe

    PH TCoE, Celgene, San Diego, United States
    Competing interests
    Mark Rolfe, Employee of Celgene.

Funding

No external funding was received for this work

Reviewing Editor

  1. Wade Harper, Harvard Medical School, United States

Version history

  1. Received: August 10, 2018
  2. Accepted: September 19, 2018
  3. Accepted Manuscript published: September 20, 2018 (version 1)
  4. 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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  1. Gang Lu
  2. Stephanie Weng
  3. Mary Matyskiela
  4. Xinde Zheng
  5. Wei Fang
  6. Scott Wood
  7. Christine Surka
  8. Reina Mizukoshi
  9. Chin-Chun Lu
  10. Derek Mendy
  11. In Sock Jang
  12. Kai Wang
  13. Mathieu Marella
  14. Suzana Couto
  15. Brian Cathers
  16. James Carmichael
  17. Philip Chamberlain
  18. Mark Rolfe
(2018)
UBE2G1 governs the destruction of cereblon neomorphic substrates
eLife 7:e40958.
https://doi.org/10.7554/eLife.40958

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