RT Journal Article
SR Electronic
T1 UBE2G1 Governs the Destruction of Cereblon Neomorphic Substrates
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 389098
DO 10.1101/389098
A1 Gang Lu
A1 Stephanie Weng
A1 Mary Matyskiela
A1 Xinde Zheng
A1 Wei Fang
A1 Scott Wood
A1 Christine Surka
A1 Reina Mizukoshi
A1 Chin-Chun Lu
A1 Derek Mendy
A1 In Sock Jang
A1 Kai Wang
A1 Mathieu Marella
A1 Suzana Couto
A1 Brian Cathers
A1 James Carmichael
A1 Philip Chamberlain
A1 Mark Rolfe
YR 2018
UL http://biorxiv.org/content/early/2018/08/09/389098.abstract
AB The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide as well as the novel cereblon modulating agents (CMs) including CC-122, CC-220 and cereblon-based proteolysis-targeting chimaeras (PROTACs) repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with an E1 ubiquitin-activating enzyme and E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the polyubiquitination of CRL4CRBN neomorphic substrates in a cereblon- and CM-dependent manner via a sequential ubiquitination mechanism: UBE2D3 transforms the neomorphic substrates into mono-ubiquitinated forms, upon which UBE2G1 catalyzes K48-linked polyubiquitin chain extension. 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, these findings suggest that loss of UBE2G1 activity might be a resistance mechanism to drugs that hijack the CRL4CRBN to eliminate disease-driving proteins, and that this resistance mechanism can be overcome by next-generation CMs that destroy the same targeted protein more effectively.