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Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):3565-3571. doi: 10.1073/pnas.1700949114. Epub 2017 Mar 20.

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates.

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
2
Celgene Corporation, San Diego, CA 92121.
3
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; deshaies@caltech.edu.
4
Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125.

Abstract

Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide, recognizes an acetyl degron of GS, resulting in ubiquitylation and degradation of GS in response to glutamine. Here, we report that valosin-containing protein (VCP)/p97 promotes the degradation of ubiquitylated GS, resulting in its accumulation in cells with compromised p97 function. Notably, p97 is also required for the degradation of all four known CRBN neo-substrates [Ikaros family zinc finger proteins 1 (IKZF1) and 3 (IKZF3), casein kinase 1α (CK1α), and the translation termination factor GSPT1] whose ubiquitylation is induced by immunomodulatory drugs. Together, these data point to an unexpectedly intimate relationship between the E3 ubiquitin ligase CRL4CRBN and p97 pathways.

KEYWORDS:

CRBN; VCP/p97; degradation; glutamine synthetase; substrates

PMID:
28320958
PMCID:
PMC5389304
DOI:
10.1073/pnas.1700949114
[Indexed for MEDLINE]
Free PMC Article

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