A Non-Canonical Function of Gβ as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation

Mol Cell. 2015 Jun 4;58(5):794-803. doi: 10.1016/j.molcel.2015.04.017. Epub 2015 May 14.

Abstract

G protein-coupled receptors (GPCRs) comprise the largest family of cell surface receptors, regulate a wide range of physiological processes, and are the major targets of pharmaceutical drugs. Canonical signaling from GPCRs is relayed to intracellular effector proteins by trimeric G proteins, composed of α, β, and γ subunits (Gαβγ). Here, we report that G protein β subunits (Gβ) bind to DDB1 and that Gβ2 targets GRK2 for ubiquitylation by the DDB1-CUL4A-ROC1 ubiquitin ligase. Activation of GPCR results in PKA-mediated phosphorylation of DDB1 at Ser645 and its dissociation from Gβ2, leading to increase of GRK2 protein. Deletion of Cul4a results in cardiac hypertrophy in male mice that can be partially rescued by the deletion of one Grk2 allele. These results reveal a non-canonical function of the Gβ protein as a ubiquitin ligase component and a mechanism of feedback regulation of GPCR signaling.

Publication types

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

MeSH terms

  • Animals
  • DNA-Binding Proteins / metabolism
  • Female
  • G-Protein-Coupled Receptor Kinase 2 / metabolism*
  • GTP-Binding Protein beta Subunits / physiology*
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Knockout
  • Nuclear Proteins / metabolism*
  • Protein Stability
  • Proteolysis
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*

Substances

  • DDB1 protein, human
  • DNA-Binding Proteins
  • DTL protein, human
  • GTP-Binding Protein beta Subunits
  • Nuclear Proteins
  • Ubiquitin-Protein Ligases
  • GRK2 protein, human
  • G-Protein-Coupled Receptor Kinase 2