Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2

Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6650-5. doi: 10.1073/pnas.0901083106. Epub 2009 Apr 10.

Abstract

Beta-arrestins are multifunctional adaptors that mediate the desensitization, internalization, and some signaling functions of seven-transmembrane receptors (7TMRs). Agonist-stimulated ubiquitination of beta-arrestin2 mediated by the E3 ubiquitin ligase Mdm2 is critical for rapid beta(2)-adrenergic receptor (beta(2)AR) internalization. We now report the discovery that the deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) binds beta-arrestin2 and leads to the deubiquitination of beta-arrestins. USP33 and Mdm2 function reciprocally and favor respectively the stability or lability of the receptor beta-arrestin complex, thus regulating the longevity and subcellular localization of receptor signalosomes. Receptors such as the beta(2)AR, previously shown to form loose complexes with beta-arrestin ("class A") promote a beta-arrestin conformation conducive for binding to the deubiquitinase, whereas the vasopressin V2R, which forms tight beta-arrestin complexes ("class B"), promotes a distinct beta-arrestin conformation that favors dissociation of the enzyme. Thus, USP33-beta-arrestin interaction is a key regulatory step in 7TMR trafficking and signal transmission from the activated receptors to downstream effectors.

Publication types

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

MeSH terms

  • Animals
  • Arrestins / metabolism*
  • Cell Line
  • Endosomes / drug effects
  • Endosomes / enzymology
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Kinetics
  • Models, Biological
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction* / drug effects
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / drug effects
  • Vasopressins / pharmacology
  • beta-Arrestins

Substances

  • Arrestins
  • Receptors, Cell Surface
  • beta-Arrestins
  • Vasopressins
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Ubiquitin-Protein Ligases
  • Extracellular Signal-Regulated MAP Kinases
  • USP33 protein, human
  • Ubiquitin Thiolesterase