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PMID:19363159

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Citation

Shenoy, SK, Modi, AS, Shukla, AK, Xiao, K, Berthouze, M, Ahn, S, Wilkinson, KD, Miller, WE and Lefkowitz, RJ (2009) 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. 106:6650-5

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.

Links

PubMed PMC2667797 Online version:10.1073/pnas.0901083106

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ARRB2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8TEY7

F

Seeded From UniProt

complete

HUMAN:ARRB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8TEY7

F

Seeded From UniProt

complete

HUMAN:UBP33

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49407

F

Seeded From UniProt

complete

HUMAN:UBP33

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P32121

F

Seeded From UniProt

complete

HUMAN:UBP33

enables

GO:0004197: cysteine-type endopeptidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:UBP33

enables

GO:0036459: thiol-dependent ubiquitinyl hydrolase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:UBP33

involved_in

GO:0008277: regulation of G protein-coupled receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP33

involved_in

GO:0016579: protein deubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP33

involved_in

GO:0070536: protein K63-linked deubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP33

involved_in

GO:0071108: protein K48-linked deubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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