Scholars@Duke publication: Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.

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

Publication , Journal Article

Shenoy, SK; Modi, AS; Shukla, AK; Xiao, K; Berthouze, M; Ahn, S; Wilkinson, KD; Miller, WE; Lefkowitz, RJ

Published in: Proc Natl Acad Sci U S A

April 21, 2009

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.

Duke Scholars

Author Robert J. Lefkowitz Medicine, Cardiology

Author Sudha Kaup Shenoy Medicine, Cardiology

Author Kunhong Xiao Medicine, Cardiology

Author Seungkirl Ahn Medicine, Cardiology

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Published In

Proc Natl Acad Sci U S A

DOI

10.1073/pnas.0901083106

EISSN

1091-6490

Publication Date

April 21, 2009

Volume

106

Issue

Start / End Page

6650 / 6655

Location

United States

Related Subject Headings

beta-Arrestins
Vasopressins
Ubiquitination
Ubiquitin-Protein Ligases
Ubiquitin Thiolesterase
Signal Transduction
Receptors, Cell Surface
Proto-Oncogene Proteins c-mdm2
Protein Transport
Protein Binding

Citation

APA

Chicago

ICMJE

MLA

NLM

Shenoy, S. K., Modi, A. S., Shukla, A. K., Xiao, K., Berthouze, M., Ahn, S., … Lefkowitz, R. J. (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(16), 6650–6655. https://doi.org/10.1073/pnas.0901083106

Shenoy, Sudha K., Aalok S. Modi, Arun K. Shukla, Kunhong Xiao, Magali Berthouze, Seungkirl Ahn, Keith D. Wilkinson, William E. Miller, and Robert J. Lefkowitz. “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, no. 16 (April 21, 2009): 6650–55. https://doi.org/10.1073/pnas.0901083106.

Shenoy SK, Modi AS, Shukla AK, Xiao K, Berthouze M, Ahn S, et al. 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.

Shenoy, Sudha K., et al. “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, vol. 106, no. 16, Apr. 2009, pp. 6650–55. Pubmed, doi:10.1073/pnas.0901083106.

Shenoy SK, Modi AS, Shukla AK, Xiao K, Berthouze M, Ahn S, Wilkinson KD, Miller WE, Lefkowitz RJ. 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):6650–6655.