UBE2G1 governs the destruction of cereblon neomorphic substrates.

ELife
Gang LuMark Rolfe

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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Citations

Jun 12, 2020·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Takumi Ito, Hiroshi Handa
Sep 19, 2019·Nature Chemical Biology·Philip P Chamberlain, Lawrence G Hamann
Feb 14, 2020·Nature·Kheewoong BaekBrenda A Schulman
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Feb 20, 2021·Proceedings of the National Academy of Sciences of the United States of America·Kenneth WuZhen-Qiang Pan
Jun 17, 2019·Pharmacology & Therapeutics·Tomoko Asatsuma-OkumuraHiroshi Handa
Apr 4, 2021·International Journal of Molecular Sciences·Xiaodi DuGuangyou Yang
Apr 4, 2021·Cell Chemical Biology·Natalie S ScholesGeorg E Winter
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Jul 2, 2021·The Biochemical Journal·Thanh Thi LeKarim P M Labib
Sep 30, 2021·Proceedings of the National Academy of Sciences of the United States of America·Thang Van Nguyen

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Methods Mentioned

BETA
ubiquitination
neddylation
gene knockout
transfection
size exclusion chromatography
PCR

Software Mentioned

Clustal W
GraphPad Prism

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