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Van Nguyen, Thang; Lee, J. Eugene; Sweredoski, Michael J.; Yang, Seung-Joo; Jeon, Seung-Je; Harrison, Joseph S.; Yim, Jung-Hyuk; Lee, Sang Ghil; Handa, Hiroshi; Kuhlman, Brian; Jeong, Ji-Seon; Reitsma, Justin M.; Park, Chul-Seung; Hess, Sonja; Deshaies, Raymond J.
Molecular cell, 03/2016, Letnik: 61, Številka: 6Journal Article
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 CRL4CRBN. 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 CRL4CRBN 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 CRL4CRBN that adjusts GS protein levels in response to glutamine and uncover a new function for lysine acetylation. Display omitted •GS is an endogenous substrate of CRL4CRBN•CRL4CRBN directly mediates the glutamine-induced degradation of GS•Glutamine-stimulated acetylation of lysines 11 and 14 regulates GS degradation•The thalidomide-binding domain of CRBN binds to an acetyllysine degron of GS Nguyen et al. demonstrate that glutamine induces acetylation of GS at lysines 11 and 14 to create an acetylated degron that binds CRL4CRBN, resulting in ubiquitylation and degradation of GS.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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