title: Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon.
abstract: 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.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Box 114-96, Pasadena, CA 91125, USA.
authors.forename: T Van
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Box 114-96, Pasadena, CA 91125, USA; Center for Bioanalysis, Division of Metrology for Quality of Life, Korea Research Institute of Standards and Science, Daejeon 305-340, Korea.
authors.forename: J Eugene
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Proteome Exploration Laboratory, Division of Biology and Biological Engineering, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sweredoski
authors.affiliation: School of Life Sciences, National Leading Research Laboratory, and Integrative Aging Research Center, Gwangju Institute Science and Technology (GIST), Gwangju 500-712, Korea.
authors.forename: Seung-Joo
authors.initials: SJ
authors.lastname: Yang
authors.affiliation: School of Life Sciences, National Leading Research Laboratory, and Integrative Aging Research Center, Gwangju Institute Science and Technology (GIST), Gwangju 500-712, Korea.
authors.forename: Seung-Je
authors.initials: SJ
authors.lastname: Jeon
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7260, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Harrison
authors.affiliation: Center for Bioanalysis, Division of Metrology for Quality of Life, Korea Research Institute of Standards and Science, Daejeon 305-340, Korea.
authors.forename: Jung-Hyuk
authors.initials: JH
authors.lastname: Yim
authors.affiliation: Center for Bioanalysis, Division of Metrology for Quality of Life, Korea Research Institute of Standards and Science, Daejeon 305-340, Korea; Department of Biochemistry, Yonsei University, Seoul 120-749, Korea.
authors.forename: Sang Ghil
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7260, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Kuhlman
authors.affiliation: Center for Bioanalysis, Division of Metrology for Quality of Life, Korea Research Institute of Standards and Science, Daejeon 305-340, Korea.
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Jeong
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Box 114-96, Pasadena, CA 91125, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Reitsma
authors.affiliation: School of Life Sciences, National Leading Research Laboratory, and Integrative Aging Research Center, Gwangju Institute Science and Technology (GIST), Gwangju 500-712, Korea.
authors.forename: Chul-Seung
authors.initials: CS
authors.lastname: Park
authors.affiliation: Proteome Exploration Laboratory, Division of Biology and Biological Engineering, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hess
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Box 114-96, Pasadena, CA 91125, USA; Howard Hughes Medical Institute. Electronic address: deshaies@caltech.edu.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D013792:Thalidomide / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D053722:Receptors, Interleukin-17
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005974:Glutamate-Ammonia Ligase; D005973:Glutamine; D007155:Immunologic Factors; D008239:Lysine; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; C502543:CRBN protein, human; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17