Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling
- University of California, San Francisco, United States
Abstract
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.
Data availability
All numerical data used to generate the figures has been included in the supporting data file. Source data for each figure panel is included as a separate worksheet in the combined excel document.
Article and author information
Author details
Funding
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.
Copyright
© 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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Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling
eLife 11:e81563.
https://doi.org/10.7554/eLife.81563
Further reading
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