TY - JOUR TI - UBE2G1 governs the destruction of cereblon neomorphic substrates AU - Lu, Gang AU - Weng, Stephanie AU - Matyskiela, Mary AU - Zheng, Xinde AU - Fang, Wei AU - Wood, Scott AU - Surka, Christine AU - Mizukoshi, Reina AU - Lu, Chin-Chun AU - Mendy, Derek AU - Jang, In Sock AU - Wang, Kai AU - Marella, Mathieu AU - Couto, Suzana AU - Cathers, Brian AU - Carmichael, James AU - Chamberlain, Philip AU - Rolfe, Mark VL - 7 PY - 2018 DA - 2018/09/20 SP - e40958 C1 - eLife 2018;7:e40958 DO - 10.7554/eLife.40958 UR - https://doi.org/10.7554/eLife.40958 AB - 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. KW - ubiquitination KW - cereblon KW - immunomodulatory drugs KW - cereblon modulating agents KW - PROTAC JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -