Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.
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.
Shenoy
Sudha K
SK
Department of Medicine, Duke University Medical Center, Box 3821, Durham, NC 27710, USA. sudha@receptor-biol.duke.edu
Modi
Aalok S
AS
Shukla
Arun K
AK
Xiao
Kunhong
K
Berthouze
Magali
M
Ahn
Seungkirl
S
Wilkinson
Keith D
KD
Miller
William E
WE
Lefkowitz
Robert J
RJ
D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D011992:Endosomes / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D014667:Vasopressins / Q000494:pharmacology; D000071557:beta-Arrestins
D019390:Arrestins; D011956:Receptors, Cell Surface; D000071557:beta-Arrestins; D014667:Vasopressins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D048049:Extracellular Signal-Regulated MAP Kinases; C449799:USP33 protein, human; D043222:Ubiquitin Thiolesterase