Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon
ORCID
Joseph Harrison: 0000-0002-2118-6524
Document Type
Article
Publication Title
Molecular Cell
Department
Chemistry
ISSN
1097-4164
Volume
61
Issue
6
DOI
10.1016/j.molcel.2016.02.032
First Page
809
Last Page
820
Publication Date
3-17-2016
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.
Recommended Citation
Nguyen, T. V.,
Lee, J. E.,
Sweredoski, M. J.,
Yang, S.,
Jeon, S.,
Harrison, J. S.,
Yim, J.,
Lee, S.,
Handa, H.,
Kuhlman, B.,
Jeong, J.,
Reitsma, J. M.,
Park, C.,
Hess, S.,
&
Deshaies, R. J.
(2016).
Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon.
Molecular Cell, 61(6), 809–820.
DOI: 10.1016/j.molcel.2016.02.032
https://scholarlycommons.pacific.edu/cop-facarticles/570
