title: FBXO44-Mediated Degradation of RGS2 Protein Uniquely Depends on a Cullin 4B/DDB1 Complex.
abstract: 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.
authors.affiliation: Department of Pharmacology & Toxicology, Michigan State University, 1355 Bogue Street, East Lansing, MI 48824, United States of America.
authors.forename: Benita
authors.initials: B
authors.lastname: Sjögren
authors.affiliation: Center for Chemical Genomics, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Swaney
authors.affiliation: Department of Pharmacology & Toxicology, Michigan State University, 1355 Bogue Street, East Lansing, MI 48824, United States of America.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
mesh_terms: D000818:Animals; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D015723:Gene Library; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D020710:RGS Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: C517832:CUL4B protein, human; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; C578089:FBXO44 protein, human; D020710:RGS Proteins; C087182:RGS2 protein, human; D034741:RNA, Small Interfering; D046988:Proteasome Endopeptidase Complex