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Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon

Nguyen, Thang Van and Lee, J. Eugene and Sweredoski, Michael J. and Yang, Seung-Joo and Jeon, Seung-Je and Harrison, Joseph S. and Yim, Jung-Hyuk and Lee, Sang Ghil and Handa, Hiroshi and Kuhlman, Brian and Jeong, Ji-Seon and Reitsma, Justin M. and Park, Chul-Seung and Hess, Sonja and Deshaies, Raymond J. (2016) Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon. Molecular Cell, 61 (6). pp. 809-820. ISSN 1097-2765. PMCID PMC4889030. doi:10.1016/j.molcel.2016.02.032.

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Cereblon (CRBN), a substrate receptor for the cullin-RING ubiquitin ligase 4 (CRL4) complex, is a direct protein target for thalidomide teratogenicity and antitumor activity of immunomodulatory drugs (IMiDs). Here we report that glutamine synthetase (GS) is an endogenous substrate of CRL4^(CRBN). Upon exposing cells to high glutamine concentration, GS is acetylated at lysines 11 and 14, yielding a degron that is necessary and sufficient for binding and ubiquitylation by CRL4^(CRBN) and degradation by the proteasome. Binding of acetylated degron peptides to CRBN depends on an intact thalidomide-binding pocket but is not competitive with IMiDs. These findings reveal a feedback loop involving CRL4^(CRBN) that adjusts GS protein levels in response to glutamine and uncover a new function for lysine acetylation.

Item Type:Article
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URLURL TypeDescription CentralArticle
Nguyen, Thang Van0000-0002-9114-7766
Lee, J. Eugene0000-0001-8625-6418
Sweredoski, Michael J.0000-0003-0878-3831
Harrison, Joseph S.0000-0002-2118-6524
Handa, Hiroshi0000-0001-6656-9521
Reitsma, Justin M.0000-0002-2700-6440
Hess, Sonja0000-0002-5904-9816
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2016 Elsevier B.V. Received: November 23, 2015; Revised: February 1, 2016; Accepted: February 26, 2016; Published: March 17, 2016. We thank W. Kaelin (Dana Farber Cancer Institute) for CRBN-KO 293FT cells. We also thank the R.J.D. lab for helpful discussions, particularly E. Blythe, R. Mosadeghi, W. den Besten, and A. Moradian (Proteome Exploration Laboratory/PEL) for their assistance, and R. Verma for insightful advice. J.E.L. was supported by a grant from National Research Council of Science and Technology (DRC-14-2-KRISS). The PEL is funded by the Gordon and Betty Moore Foundation (Grant GBMF775) and the Beckman Institute. T.V.N is supported by the Vietnam Education Foundation, a Brian D. Novis Research Award from the International Myeloma Foundation, and the Leukemia & Lymphoma Society. R.J.D. is an Investigator of the Howard Hughes Medical Institute, and this work was supported in part by HHMI. Author Contributions: T.V.N. and R.J.D., study conception and design, data analysis, and drafting of the manuscript with editorial assistance from other authors. T.V.N., all cellular and molecular experiments. J.E.L., mass spectrometry experiments in Figures 1A and S5 and Table S1. M.J.S. and S.H., mass spectrometry data analysis. M.J.S., protein sequence analysis. J.M.R. and S.G.L., analysis of the mass spectrometry data in Figure S5. J.S.H. and B.K., computational predictions of effects of mutations in the GS-binding site of CRBN and analysis of human GS structure in Figures S7B and S7C. J.-H.Y. and J.-S.J., quantification of glutamine and glutamate in serum and analysis of data in Figure 2G and Table S3. S.-J.Y., S.-J. J., and C.-S.P., mouse studies in Figures 2D–2F. H.H. provided essential reagents.
Funding AgencyGrant Number
National Research Council of Science and TechnologyDRC-14-2-KRISS
Gordon and Betty Moore Foundation775
Caltech Beckman InstituteUNSPECIFIED
Vietnam Education FoundationUNSPECIFIED
International Myeloma FoundationUNSPECIFIED
Leukemia and Lymphoma SocietyUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:6
PubMed Central ID:PMC4889030
Record Number:CaltechAUTHORS:20160321-131029451
Persistent URL:
Official Citation:T. Van Nguyen, J. Eugene Lee, Michael J. Sweredoski, Seung-Joo Yang, Seung-Je Jeon, Joseph S. Harrison, Jung-Hyuk Yim, Sang Ghil Lee, Hiroshi Handa, Brian Kuhlman, Ji-Seon Jeong, Justin M. Reitsma, Chul-Seung Park, Sonja Hess, Raymond J. Deshaies, Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon, Molecular Cell, Volume 61, Issue 6, 17 March 2016, Pages 809-820, ISSN 1097-2765, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:65539
Deposited By: Tony Diaz
Deposited On:22 Mar 2016 01:18
Last Modified:05 May 2022 18:15

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