Sjögren Benita, Swaney Steven, Neubig Richard R
Department of Pharmacology & Toxicology, Michigan State University, 1355 Bogue Street, East Lansing, MI 48824, United States of America.
Center for Chemical Genomics, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109, United States of America.
PLoS One. 2015 May 13;10(5):e0123581. doi: 10.1371/journal.pone.0123581. eCollection 2015.
The ubiquitin-proteasome system for protein degradation plays a major role in regulating cell function and many signaling proteins are tightly controlled by this mechanism. Among these, Regulator of G Protein Signaling 2 (RGS2) is a target for rapid proteasomal degradation, however, the specific enzymes involved are not known. Using a genomic siRNA screening approach, we identified a novel E3 ligase complex containing cullin 4B (CUL4B), DNA damage binding protein 1 (DDB1) and F-box protein 44 (FBXO44) that mediates RGS2 protein degradation. While the more typical F-box partners CUL1 and Skp1 can bind FBXO44, that E3 ligase complex does not bind RGS2 and is not involved in RGS2 degradation. These observations define an unexpected DDB1/CUL4B-containing FBXO44 E3 ligase complex. Pharmacological targeting of this mechanism provides a novel therapeutic approach to hypertension, anxiety, and other diseases associated with RGS2 dysregulation.
用于蛋白质降解的泛素 - 蛋白酶体系统在调节细胞功能中起主要作用，许多信号蛋白受此机制严格控制。其中，G蛋白信号调节因子2（RGS2）是蛋白酶体快速降解的靶点，然而，具体涉及的酶尚不清楚。我们采用基因组siRNA筛选方法，鉴定出一种新型E3连接酶复合物，其包含cullin 4B（CUL4B）、DNA损伤结合蛋白1（DDB1）和F - 盒蛋白44（FBXO44），该复合物介导RGS2蛋白的降解。虽然更典型的F - 盒伴侣CUL1和Skp1可以结合FBXO44，但该E3连接酶复合物不结合RGS2，也不参与RGS2的降解。这些观察结果定义了一种意想不到的含DDB1/CUL4B的FBXO44 E3连接酶复合物。对该机制进行药物靶向治疗为高血压、焦虑症和其他与RGS2失调相关的疾病提供了一种新的治疗方法。
