UBE2G1 governs the destruction of cereblon neomorphic substrates
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2018-09-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/40958 |
| _version_ | 1811201143718543360 |
|---|---|
| author | Gang Lu Stephanie Weng Mary Matyskiela Xinde Zheng Wei Fang Scott Wood Christine Surka Reina Mizukoshi Chin-Chun Lu Derek Mendy In Sock Jang Kai Wang Mathieu Marella Suzana Couto Brian Cathers James Carmichael Philip Chamberlain Mark Rolfe |
| author_facet | Gang Lu Stephanie Weng Mary Matyskiela Xinde Zheng Wei Fang Scott Wood Christine Surka Reina Mizukoshi Chin-Chun Lu Derek Mendy In Sock Jang Kai Wang Mathieu Marella Suzana Couto Brian Cathers James Carmichael Philip Chamberlain Mark Rolfe |
| author_sort | Gang Lu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:15:50Z |
| format | Article |
| id | doaj.art-8ea06e542c9e4cde89d15b97eac42be1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:15:50Z |
| publishDate | 2018-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8ea06e542c9e4cde89d15b97eac42be12022-12-22T03:52:15ZengeLife Sciences Publications LtdeLife2050-084X2018-09-01710.7554/eLife.40958UBE2G1 governs the destruction of cereblon neomorphic substratesGang Lu0https://orcid.org/0000-0002-2138-1522Stephanie Weng1Mary Matyskiela2Xinde Zheng3Wei Fang4Scott Wood5Christine Surka6Reina Mizukoshi7Chin-Chun Lu8Derek Mendy9In Sock Jang10Kai Wang11Mathieu Marella12Suzana Couto13Brian Cathers14James Carmichael15Philip Chamberlain16Mark Rolfe17Celgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesCelgene Corporation, San Diego, United StatesThe 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.https://elifesciences.org/articles/40958ubiquitinationcereblonimmunomodulatory drugscereblon modulating agentsPROTAC |
| spellingShingle | Gang Lu Stephanie Weng Mary Matyskiela Xinde Zheng Wei Fang Scott Wood Christine Surka Reina Mizukoshi Chin-Chun Lu Derek Mendy In Sock Jang Kai Wang Mathieu Marella Suzana Couto Brian Cathers James Carmichael Philip Chamberlain Mark Rolfe UBE2G1 governs the destruction of cereblon neomorphic substrates eLife ubiquitination cereblon immunomodulatory drugs cereblon modulating agents PROTAC |
| title | UBE2G1 governs the destruction of cereblon neomorphic substrates |
| title_full | UBE2G1 governs the destruction of cereblon neomorphic substrates |
| title_fullStr | UBE2G1 governs the destruction of cereblon neomorphic substrates |
| title_full_unstemmed | UBE2G1 governs the destruction of cereblon neomorphic substrates |
| title_short | UBE2G1 governs the destruction of cereblon neomorphic substrates |
| title_sort | ube2g1 governs the destruction of cereblon neomorphic substrates |
| topic | ubiquitination cereblon immunomodulatory drugs cereblon modulating agents PROTAC |
| url | https://elifesciences.org/articles/40958 |
| work_keys_str_mv | AT ganglu ube2g1governsthedestructionofcereblonneomorphicsubstrates AT stephanieweng ube2g1governsthedestructionofcereblonneomorphicsubstrates AT marymatyskiela ube2g1governsthedestructionofcereblonneomorphicsubstrates AT xindezheng ube2g1governsthedestructionofcereblonneomorphicsubstrates AT weifang ube2g1governsthedestructionofcereblonneomorphicsubstrates AT scottwood ube2g1governsthedestructionofcereblonneomorphicsubstrates AT christinesurka ube2g1governsthedestructionofcereblonneomorphicsubstrates AT reinamizukoshi ube2g1governsthedestructionofcereblonneomorphicsubstrates AT chinchunlu ube2g1governsthedestructionofcereblonneomorphicsubstrates AT derekmendy ube2g1governsthedestructionofcereblonneomorphicsubstrates AT insockjang ube2g1governsthedestructionofcereblonneomorphicsubstrates AT kaiwang ube2g1governsthedestructionofcereblonneomorphicsubstrates AT mathieumarella ube2g1governsthedestructionofcereblonneomorphicsubstrates AT suzanacouto ube2g1governsthedestructionofcereblonneomorphicsubstrates AT briancathers ube2g1governsthedestructionofcereblonneomorphicsubstrates AT jamescarmichael ube2g1governsthedestructionofcereblonneomorphicsubstrates AT philipchamberlain ube2g1governsthedestructionofcereblonneomorphicsubstrates AT markrolfe ube2g1governsthedestructionofcereblonneomorphicsubstrates |