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Published April 4, 2017 | Published + Supplemental Material
Journal Article Open

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates


Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide, recognizes an acetyl degron of GS, resulting in ubiquitylation and degradation of GS in response to glutamine. Here, we report that valosin-containing protein (VCP)/p97 promotes the degradation of ubiquitylated GS, resulting in its accumulation in cells with compromised p97 function. Notably, p97 is also required for the degradation of all four known CRBN neo-substrates [Ikaros family zinc finger proteins 1 (IKZF1) and 3 (IKZF3), casein kinase 1α (CK1α), and the translation termination factor GSPT1] whose ubiquitylation is induced by immunomodulatory drugs. Together, these data point to an unexpectedly intimate relationship between the E3 ubiquitin ligase CRL4^(CRBN) and p97 pathways.

Additional Information

© 2017 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Raymond J. Deshaies, March 1, 2017 (sent for review January 19, 2017; reviewed by Hemmo Meyer and Yihong Ye). Published ahead of print March 20, 2017. We thank Dr. William Kaelin (Dana Farber Cancer Institute) for the CRBN-KO 293FT cell line and plasmids; Dr. Francesco Parlati (Calithera Biosciences) for L363 cells; Dr. David Chan (California Institute of Technology) for plasmids; Dr. Yuyong Ma and Dr. Seth Cohen (University of California, San Diego) for CB-5083; and all the members of the R.J.D. laboratory for helpful discussions, particularly E. Blythe, R. Verma, and W. den Besten. T.V.N. is supported by a Fellow Award from the Leukemia & Lymphoma Society. R.J.D. is an Investigator of the Howard Hughes Medical Institute (HHMI), and this work was supported in part by the HHMI and in part by NIH Grant GM-065997. This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2016. Author contributions: T.V.N. and R.J.D. designed research; T.V.N., J.L., C.-C.J.L., and J.L.M. performed research; T.V.N. contributed new reagents/analytic tools; T.V.N., G.L., B.E.C., and R.J.D. analyzed data; and T.V.N. and R.J.D. wrote the paper. Reviewers: H.M., University of Duisburg-Essen; and Y.Y., National Institutes of Health. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1700949114/-/DCSupplemental.

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Published - PNAS-2017-Nguyen-3565-71.pdf

Supplemental Material - pnas.201700949SI.pdf


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