Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Celgene Corporation, San Diego, CA 92121.
Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):3565-3571. doi: 10.1073/pnas.1700949114. Epub 2017 Mar 20.
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 CRL4 and p97 pathways.
谷氨酰胺合成酶（GS）通过催化谷氨酸和氨合成谷氨酰胺，在代谢中发挥重要作用。我们最近的研究表明，CRBN 是一种直接的蛋白质靶标，对于免疫调节药物（如沙利度胺、来那度胺和泊马度胺）的致畸和抗肿瘤活性，CRBN 识别 GS 的乙酰化降解结构域，导致 GS 的泛素化和降解，以响应谷氨酰胺。在这里，我们报告称，含缬氨酸蛋白（VCP）/p97 促进了泛素化 GS 的降解，导致其在 p97 功能受损的细胞中积累。值得注意的是，p97 也需要降解所有四个已知的 CRBN 新型底物（Ikaros 家族锌指蛋白 1（IKZF1）和 3（IKZF3）、酪蛋白激酶 1α（CK1α）和翻译终止因子 GSPT1），这些底物的泛素化是由免疫调节药物诱导的。这些数据共同表明，E3 泛素连接酶 CRL4 和 p97 途径之间存在着出人意料的密切关系。
