p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates.
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 CRL4CRBNand p97 pathways.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Thang Van
TV
Nguyen
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Jing
J
Li
Celgene Corporation, San Diego, CA 92121.
Chin-Chun Jean
CJ
Lu
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Jennifer L
JL
Mamrosh
Celgene Corporation, San Diego, CA 92121.
Gang
G
Lu
Celgene Corporation, San Diego, CA 92121.
Brian E
BE
Cathers
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; deshaies@caltech.edu.|Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125.
Raymond J
RJ
Deshaies
D048868:Adaptor Proteins, Signal Transducing; D047389:Casein Kinase I / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D005973:Glutamine / Q000494:pharmacology*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism; D061986:MCF-7 Cells; D010447:Peptide Hydrolases / Q000378:metabolism*; D010454:Peptide Termination Factors / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D000074405:Valosin Containing Protein / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; C497239:IKZF1 protein, human; C106285:IKZF3 protein, human; D010454:Peptide Termination Factors; C087971:peptide-chain-release factor 3; D005973:Glutamine; D051740:Ikaros Transcription Factor; D044767:Ubiquitin-Protein Ligases; D047389:Casein Kinase I; D010447:Peptide Hydrolases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; D005974:Glutamate-Ammonia Ligase
CRBN; VCP/p97; degradation; glutamine synthetase; substrates