UBE2G1 governs the destruction of cereblon neomorphic substrates
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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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Several functional genomics campaigns have helped map how the repertoire of CRLs and their regulators shape degrader efficacy, outlining putative resistance mechanisms.
“Several functional genomics campaigns in recent years have helped map how the repertoire of CLRs and their regulators shape degrader efficacy, thus also outlining putative resistance mechanisms.141-151”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [143]
ZF2 mediates tight immunomodulatory-drug dependent interaction sufficient to target degradation.
“Our assay for CRL4CRBN ubiquitylation of IKZF was established based on findings that ZF2 mediates tight immunomodulatory-drug dependent interaction sufficient to target degradation, UBE2D3 contributes to stability of CRL4CRBN neomorphic substrates in cells57,60,61.”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [61]
UBE2D3 contributes to stability of CRL4CRBN neomorphic substrates in cells.
“Our assay for CRL4CRBN ubiquitylation of IKZF was established based on findings that ZF2 mediates tight immunomodulatory-drug dependent interaction sufficient to target degradation, UBE2D3 contributes to stability of CRL4CRBN neomorphic substrates in cells57,60,61.”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [61]
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Cites
Hershko, A., & Ciechanover, A. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.425 · Cited by 8,840 · see citing works
Mechanisms Underlying Ubiquitination
Pickart, C. M. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.503 · Cited by 3,731 · see citing works
Komander, D., & Rape, M. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060310-170328 · Cited by 3,679 · see citing works
Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141230798 · Cited by 2,609 · see citing works
Function and regulation of cullin–RING ubiquitin ligases
Petroski, M. D., & Deshaies, R. J. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1547 · Cited by 2,148 · see citing works
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
Soucy, T. A., Smith, P. G., Milhollen, M. A., Berger, A. J., Gavin, J. M., Adhikari, S., Brownell, J. E., Burke, K. E., Cardin, D. P., Critchley, S., et al. (2009) · Nature · doi:10.1038/nature07884 · Cited by 1,990 · see citing works
Self-citationLenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., Svinkina, T., Heckl, D., Comer, E., Li, X., et al. (2014) · Science · doi:10.1126/science.1244851 · Cited by 1,879 · see citing works
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760 · see citing works
The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins
Lu, G., Middleton, R. E., Sun, H., Naniong, M., Ott, C. J., Mitsiades, C. S., Wong, K.-K., Bradner, J. E., & Kaelin, W. G. (2014) · Science · doi:10.1126/science.1244917 · Cited by 1,583 · see citing works
Self-citationSkowyra, D., Craig, K. L., Tyers, M., Elledge, S. J., & Harper, J. W. (1997) · Cell · doi:10.1016/s0092-8674(00)80403-1 · Cited by 1,227 · see citing works
Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide
Fischer, E. S., Böhm, K., Lydeard, J. R., Yang, H., Stadler, M. B., Cavadini, S., Nagel, J., Serluca, F., Acker, V., Lingaraju, G. M., et al. (2014) · Nature · doi:10.1038/nature13527 · Cited by 1,141 · see citing works
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
Zengerle, M., Chan, K.-H., & Ciulli, A. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00216 · Cited by 1,056 · see citing works
Feldman, R. M. R., Correll, C. C., Kaplan, K. B., & Deshaies, R. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80404-3 · Cited by 872 · see citing works
Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS
Krönke, J., Fink, E. C., Hollenbach, P. W., MacBeth, K. J., Hurst, S. N., Udeshi, N. D., Chamberlain, P. P., Mani, D. R., Man, H. W., Gandhi, A. K., et al. (2015) · Nature · doi:10.1038/nature14610 · Cited by 863 · see citing works
Self-citationA novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase
Matyskiela, M. E., Lu, G., Ito, T., Pagarigan, B., Lu, C.-C., Miller, K., Fang, W., Wang, N.-Y., Nguyen, D., Houston, J., et al. (2016) · Nature · doi:10.1038/nature18611 · Cited by 701 · see citing works
Self-citationStructural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase
Petzold, G., Fischer, E. S., & Thomä, N. H. (2016) · Nature · doi:10.1038/nature16979 · Cited by 620 · see citing works
Gandhi, A. K., Kang, J., Havens, C. G., Conklin, T., Ning, Y., Wu, L., Ito, T., Ando, H., Waldman, M. F., Thakurta, A., et al. (2014) · British Journal of Haematology · doi:10.1111/bjh.12708 · Cited by 619 · see citing works
Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide
Zhu, Y. X., Braggio, E., Shi, C.-X., Bruins, L. A., Schmidt, J. E., Van Wier, S., Chang, X.-B., Bjorklund, C. C., Fonseca, R., Bergsagel, P. L., et al. (2011) · Blood · doi:10.1182/blood-2011-05-356063 · Cited by 607 · see citing works
Targeted protein degradation by PROTACs
Neklesa, T. K., Winkler, J. D., & Crews, C. M. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.027 · Cited by 599 · see citing works
Mechanism of Ubiquitin-Chain Formation by the Human Anaphase-Promoting Complex
Jin, L., Williamson, A. P., Banerjee, S., Philipp, I., & Rapé, M. (2008) · Cell · doi:10.1016/j.cell.2008.04.012 · Cited by 536 · see citing works
Chamberlain, P. P., Lopez-Girona, A., Miller, K., Carmel, G., Pagarigan, B., Chie-Leon, B., Rychak, E., Corral, L. G., Ren, Y. J., Wang, M., et al. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2874 · Cited by 531 · see citing works
Self-citationNedd8 on cullin: building an expressway to protein destruction
Pan, Z., Kentsis, A., Dias, D. C., Yamoah, K., & Wu, K. K.-Y. (2004) · Oncogene · doi:10.1038/sj.onc.1207414 · Cited by 430 · see citing works
Drugging the undruggables: exploring the ubiquitin system for drug development
Huang, X., & Dixit, V. M. (2016) · Cell Research · doi:10.1038/cr.2016.31 · Cited by 427 · see citing works
A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos
Matyskiela, M. E., Zhang, W., Man, H.-W., Muller, G., Khambatta, G., Baculi, F., Hickman, M., LeBrun, L., Pagarigan, B., Carmel, G., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01921 · Cited by 309 · see citing works
Self-citationIdentification of the Activating and Conjugating Enzymes of the NEDD8 Conjugation Pathway
Gong, L., & Yeh, E. T. H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.17.12036 · Cited by 273 · see citing works
Kortüm, K. M., Mai, E. K., Hanafiah, N. H., Shi, C.-X., Zhu, Y.-X., Bruins, L., Barrio, S., Jedlowski, P., Merz, M., Xu, J., et al. (2016) · Blood · doi:10.1182/blood-2016-02-698092 · Cited by 255 · see citing works
Sequential E2s Drive Polyubiquitin Chain Assembly on APC Targets
Rodrigo-Brenni, M. C., & Morgan, D. O. (2007) · Cell · doi:10.1016/j.cell.2007.05.027 · Cited by 250 · see citing works
Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation
Scott, D. C., Rhee, D. Y., Duda, D. M., Kelsall, I. R., Olszewski, J. L., Paulo, J. A., de Jong, A., Ovaa, H., Alpi, A. F., Harper, J. W., et al. (2016) · Cell · doi:10.1016/j.cell.2016.07.027 · Cited by 229 · see citing works
A ubiquitin ligase transfers preformed polyubiquitin chains from a conjugating enzyme to a substrate
Li, W., Tu, D., Brünger, A. T., & Ye, Y. (2007) · Nature · doi:10.1038/nature05542 · Cited by 227 · see citing works
Targeted Protein Degradation by Small Molecules
Bondeson, D. P., & Crews, C. M. (2017) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103507 · Cited by 207 · see citing works
Hagner, P. R., Man, H.-W., Fontanillo, C., Wang, M., Couto, S., Breider, M., Bjorklund, C., Havens, C. G., Lu, G., Rychak, E., et al. (2015) · Blood · doi:10.1182/blood-2015-02-628669 · Cited by 203 · see citing works
Self-citationDeshaies, R. J. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1887 · Cited by 162 · see citing works
Priming and Extending: A UbcH5/Cdc34 E2 Handoff Mechanism for Polyubiquitination on a SCF Substrate
Wu, K., Kovacev, J., & Pan, Z.-Q. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.02.025 · Cited by 126 · see citing works
Nuclear‐specific degradation of Far1 is controlled by the localization of the F‐box protein Cdc4
Blondel, M., Galan, J., Chi, Y., Lafourcade, C., Longaretti, C., Deshaies, R. J., & Peter, M. (2000) · The EMBO Journal · doi:10.1093/emboj/19.22.6085 · Cited by 110 · see citing works
Separate SCFCDC4 recognition elements target Cdc6 for proteolysis in S phase and mitosis
Perkins, G. R., Drury, L. S., & Diffley, J. F. X. (2001) · The EMBO Journal · doi:10.1093/emboj/20.17.4836 · Cited by 108 · see citing works
Cloning of the human homolog of the CDC34 cell cycle gene by complementation in yeast.
Plon, S. E., Leppig, K. A., Do, H. N., & Groudine, M. T. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.22.10484 · Cited by 88 · see citing works
Phosphorylation of ETS1 by Src Family Kinases Prevents Its Recognition by the COP1 Tumor Suppressor
Lü, G., Zhang, Q. H., Huang, Y., Song, J., Tomaino, R., Ehrenberger, T., Lim, E., Liu, W., Bronson, R. T., Bowden, M., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.06.026 · Cited by 86 · see citing works
Lehti, M., Donelan, E. M., Abplanalp, W., Al-Massadi, O., Habegger, K., Weber, J., Ress, C., Mansfeld, J., Somvanshi, S., Trivedi, C. J., et al. (2013) · Circulation · doi:10.1161/circulationaha.113.001551 · Cited by 84 · see citing works
Schafer, P. H., Ye, Y., Wu, L., Kosek, J., Ringheim, G., Yang, Z., Liu, L., Thomas, M., Palmisano, M., & Chopra, R. (2018) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-212916 · Cited by 78 · see citing works
How I treat first relapse of myeloma
Harousseau, J. L., & Attal, M. (2017) · Blood · doi:10.1182/blood-2017-03-726703 · Cited by 66 · see citing works
Nakayama, Y., Kosek, J., Capone, L., Hur, E. M., Schafer, P. H., & Ringheim, G. E. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601725 · Cited by 54 · see citing works
Shibata, E., Abbas, T., Huang, X., Wohlschlegel, J. A., & Dutta, A. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.05496-11 · Cited by 46 · see citing works
Protein degradation: a validated therapeutic strategy with exciting prospects
Lebraud, H., & Heightman, T. D. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170030 · Cited by 29 · see citing works
Choi, Y., Lee, Y., Lee, S., Shi, L., Ha, J.-H., Cheong, H., Cheong, C., Cohen, R. E., & Ryu, K. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.624809 · Cited by 28 · see citing works
Establishment and characterization of two human myeloma cell lines secreting kappa light chains.
Eton, O. E., Scheinberg, D. A., & Houghton, A. (1989) · PubMed · Cited by 24 · see citing works
Kleiger, G., & Deshaies, R. J. (2016) · Cell · doi:10.1016/j.cell.2016.08.014 · Cited by 14 · see citing works
Jang, S., Elsasser, S., Campbell, J. L., et al. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3540655 · Cited by 12 · see citing works
Qian, X., Dimopoulos, M. A., Amatangelo, M. D., Bjorklund, C. C., Towfic, F., Flynt, E., Weisel, K. C., Ocio, E. M., Yu, X., Peluso, T., et al. (2018) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2018.1485915 · Cited by 12 · see citing works
Jang, S., Elsasser, S., Campbell, J. L., et al. (2001) · Biochemical Journal · doi:10.1042/bj3540655 · Cited by 5 · see citing works
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Chamberlain, P. P., & Hamann, L. G. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0362-y · Cited by 489 · see citing works
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Baek, K., Krist, D. T., Prabu, J. R., Hill, S., Klügel, M., Neumaier, L.-M., von Gronau, S., Kleiger, G., & Schulman, B. A. (2020) · Nature · doi:10.1038/s41586-020-2000-y · Cited by 270 · see citing works
Surka, C., Jin, L., Mbong, N., Lu, C.-C., Jang, I. S., Rychak, E., Mendy, D., Clayton, T., Tindall, E., Hsu, C., et al. (2021) · Blood · doi:10.1182/blood.2020008676 · Cited by 229 · see citing works
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Hsia, O., Hinterndorfer, M., Cowan, A. D., Iso, K., Ishida, T., Sundaramoorthy, R., Nakasone, M. A., Imrichova, H., Schätz, C., Rukavina, A., et al. (2024) · Nature · doi:10.1038/s41586-024-07089-6 · Cited by 222 · see citing works
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Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., & Mayor-Ruiz, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00197g · Cited by 200 · see citing works
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Hanzl, A., Casement, R., Imrichova, H., Hughes, S. J., Barone, E., Testa, A., Bauer, S., Wright, J., Brand, M., Ciulli, A., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-022-01177-2 · Cited by 133 · see citing works
Mayor-Ruiz, C., Jaeger, M. G., Bauer, S., Brand, M., Sin, C., Hanzl, A., Mueller, A. C., Menche, J., & Winter, G. E. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.013 · Cited by 119 · see citing works
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Gosavi, P. M., Ngan, K. C., Yeo, M. J. R., Su, C., Li, J., Lue, N. Z., Hoenig, S. M., & Liau, B. B. (2022) · ACS Central Science · doi:10.1021/acscentsci.1c01603 · Cited by 56 · see citing works
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- Authors
- Lu, G., Weng, S., Matyskiela, M., Zheng, X., Fang, W., Wood, S., Surka, C., Mizukoshi, R., Lu, C.-C., Mendy, D., Jang, I. S., Wang, K., Marella, M., Couto, S., Cathers, B., Carmichael, J., Chamberlain, P., & Rolfe, M.
- Affiliations
- Celgene Corporation, San Diego, United States
- Corresponding author
- Lu, Gang
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-09-20
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6185104
- OpenAlex
- W2885735594
- Cited by
- 78
- References
- 49
- Citations by year
- 2026: 8 · 2025: 2 · 2024: 16 · 2023: 6 · 2022: 17 · 2021: 15 · 2020: 7 · 2019: 7
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Celgene
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Keywords
- UBE2D3, lenalidomide, pomalidomide, K48-linked polyubiquitination, IKZF1, IKZF3, multiple myeloma, drug resistance, protein degradation
- MeSH terms
- Amino Acid Sequence, Humans, Peptide Hydrolases, Substrate Specificity, Thalidomide, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Ikaros Transcription Factor, Receptors, Interleukin-17, Ubiquitination, HEK293 Cells, Proteolysis
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