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

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

doi:10.1016/j.molcel.2016.02.032

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

Mol Cell. 2016 Mar 17;61(6):809-20. doi: 10.1016/j.molcel.2016.02.032.

Authors

Affiliations

¹ Division of Biology and Biological Engineering, California Institute of Technology, Box 114-96, Pasadena, CA 91125, USA.
² 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.
³ Proteome Exploration Laboratory, Division of Biology and Biological Engineering, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.
⁴ School of Life Sciences, National Leading Research Laboratory, and Integrative Aging Research Center, Gwangju Institute Science and Technology (GIST), Gwangju 500-712, Korea.
⁵ Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7260, USA.
⁶ Center for Bioanalysis, Division of Metrology for Quality of Life, Korea Research Institute of Standards and Science, Daejeon 305-340, Korea.
⁷ 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.
⁸ Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
⁹ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Adaptor Proteins, Signal Transducing
Glutamate-Ammonia Ligase / metabolism*
Glutamine / metabolism
HEK293 Cells
Humans
Immunologic Factors / metabolism*
Lysine / metabolism
Peptide Hydrolases / metabolism*
Proteasome Endopeptidase Complex / metabolism
Proteolysis
Thalidomide / metabolism
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination

Substances

Adaptor Proteins, Signal Transducing
CRBN protein, human
IL17RB protein, human
Immunologic Factors
Glutamine
Thalidomide
Ubiquitin-Protein Ligases
Peptide Hydrolases
Proteasome Endopeptidase Complex
Glutamate-Ammonia Ligase
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding