Nguyen TV, Lee JE, Sweredoski MJ, Yang SJ, Jeon SJ, Harrison JS, Yim JH, Lee SG, Handa H, Kuhlman B, Jeong JS, Reitsma JM, Park CS, Hess S, Deshaies RJ

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 ...

Read More

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.

Date: Mar. 17, 2016

View in: Pubmed Google Scholar

193040