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s protein binds ubiquitin to regulate epidermal growth factor receptor endosomal sorting

  1. Christine Lavoiea,1
  1. aDepartment of Pharmacology-Physiology, Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4;
  2. bDepartment of Biochemistry, Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada, J1H 5N4
  1. Edited by Pietro De Camilli, Howard Hughes Medical Institute, Yale University, New Haven, CT, and approved November 3, 2017 (received for review May 31, 2017)

Significance

s protein is classically known as a signaling component of cell surface G protein-coupled receptor transduction pathways. However, Gαs has also been localized on endosomes, where it plays a role in receptor sorting to lysosomes. How Gαs regulates this trafficking step is unclear. Although Gαs structure has been known for years, we found a motif in Gαs that allows its interaction with ubiquitin, a key signal for cargo sorting to the lysosomal pathway. We show that disrupting the ubiquitin-interacting motif (UIM) in Gαs impairs its interaction with components of the endosomal sorting machinery and the lysosomal degradation of epidermal growth factor receptor. This study provides molecular insights on the mechanism by which Gαs is involved in this noncanonical function.

Abstract

The Gαs subunit is classically involved in the signal transduction of G protein-coupled receptors (GPCRs) at the plasma membrane. Recent evidence has revealed noncanonical roles for Gαs in endosomal sorting of receptors to lysosomes. However, the mechanism of action of Gαs in this sorting step is still poorly characterized. Here, we report that Gαs interacts with ubiquitin to regulate the endosomal sorting of receptors for lysosomal degradation. We reveal that the N-terminal extremity of Gαs contains a ubiquitin-interacting motif (UIM), a sorting element usually found in the endosomal sorting complex required for transport (ESCRT) machinery responsible for sorting ubiquitinated receptors into intraluminal vesicles (ILVs) of multivesicular bodies (MVBs). Mutation of the UIM in Gαs confirmed the importance of ubiquitin interaction for the sorting of epidermal growth factor receptor (EGFR) into ILVs for lysosomal degradation. These findings demonstrate a role for Gαs as an integral component of the ubiquitin-dependent endosomal sorting machinery and highlight the dual role of Gαs in receptor trafficking and signaling for the fine-tuning of the cellular response.

Footnotes

  • ?1To whom correspondence should be addressed. Email: christine.l.lavoie{at}usherbrooke.ca.
  • Author contributions: X.L. and C.L. designed research; X.L., D.L., B.H., and C.L. performed research; X.L., D.L., B.H., R.L., P.L., and C.L. analyzed data; and X.L., D.L., and C.L. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1708215114/-/DCSupplemental.

Published under the PNAS license.

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