FBXO44-Mediated Degradation of RGS2 Protein Uniquely Depends on a Cullin 4B/DDB1 Complex

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cullin Proteins / antagonists & inhibitors
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism*
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • F-Box Proteins / antagonists & inhibitors
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Gene Expression Regulation
  • Gene Library
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / chemistry
  • Myocardium / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Proteolysis
  • RGS Proteins / antagonists & inhibitors
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Ubiquitination


  • CUL4B protein, human
  • Cullin Proteins
  • DDB1 protein, human
  • DNA-Binding Proteins
  • F-Box Proteins
  • FBXO44 protein, human
  • RGS Proteins
  • RGS2 protein, human
  • RNA, Small Interfering
  • Proteasome Endopeptidase Complex