Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling
β-arrestins are master regulators of cellular signaling that operate by desensitizing ligand-activated G protein-coupled receptors (GPCRs) at the plasma membrane and promoting their subsequent endocytosis. The endocytic activity of β-arrestins is ligand-dependent, triggered by GPCR binding, and increasingly recognized to have a multitude of downstream signaling and trafficking consequences that are specifically programmed by the bound GPCR. However, only one biochemical 'mode' for GPCR-mediated triggering of the endocytic activity is presently known- displacement of the β-arrestin C-terminus (CT) to expose CCP-binding determinants that are masked in the inactive state. Here we revise this view by uncovering a second mode of GPCR-triggered endocytic activity that is independent of the β-arrestin CT and, instead, requires the cytosolic base of the β-arrestin C-lobe (CLB). We further show each of the discrete endocytic modes is triggered in a receptor-specific manner, with GPCRs that bind β-arrestin transiently ('class A') primarily triggering the CLB-dependent mode and GPCRs that bind more stably ('class B') triggering both the CT and CLB -dependent modes in combination. Moreover, we show that different modes have opposing effects on the net signaling output of receptors- with the CLB-dependent mode promoting rapid signal desensitization and the CT-dependent mode enabling prolonged signaling. Together, these results fundamentally revise understanding of how β-arrestins operate as efficient endocytic adaptors while facilitating diversity and flexibility in the control of cell signaling.
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Article and author information
NIH Office of the Director (DP5OD023048)
- Aashish Manglik
National Institutes of Health (R01DA010711)
- Mark von Zastrow
National Institutes of Health (R01DA012864)
- Mark von Zastrow
American Heart Association (19PRE34380570)
- Benjamin Barsi-Rhyne
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Suzanne R Pfeffer, Stanford University, United States
- Received: July 2, 2022
- Preprint posted: July 15, 2022 (view preprint)
- Accepted: October 14, 2022
- Accepted Manuscript published: October 17, 2022 (version 1)
- Version of Record published: November 22, 2022 (version 2)
© 2022, Barsi-Rhyne et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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