Ubiquitylation and activation of a Rab GTPase is promoted by a β2AR-HACE1 complex

Véronik Lachance, Jade Degrandmaison, Sébastien Marois, Mélanie Robitaille, Samuel Génier, Stéphanie Nadeau, Stéphane Angers, Jean Luc Parent

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

We and others have shown that trafficking of G-protein-coupled receptors is regulated by Rab GTPases. Cargo-mediated regulation of vesicular transport has received great attention lately. Rab GTPases, which form the largest branch of the Ras GTPase superfamily, regulate almost every step of vesicle-mediated trafficking. Rab GTPases are well-recognized targets of human diseases but their regulation and the mechanisms connecting them to cargo proteins are still poorly understood. Here, we show by overexpression and depletion studies that HACE1, a HECTdomain-containing ubiquitin ligase, promotes the recycling of the b2-adrenergic receptor (β2AR), a prototypical G-protein-coupled receptor, through a Rab11a-dependent mechanism. Interestingly, the β2AR in conjunction with HACE1 triggered ubiquitylation of Rab11a, as observed by western blot analysis. LC-MS/MS experiments determined that Rab11a is ubiquitylated on Lys145. A Rab11a-K145R mutant failed to undergo β2AR-HACE1-induced ubiquitylation and inhibited the HACE1-mediated recycling of the β2AR. Rab11a, but not Rab11a-K145R, was activated by β2AR- HACE1, indicating that ubiquitylation of Lys145 is involved in activation of Rab11a. Co-expression of β2AR-HACE1 also potentiated ubiquitylation of Rab6a and Rab8a, but not of other Rab GTPases that were tested. We report a novel regulatory mechanism of Rab GTPases through their ubiquitylation, with associated functional effects demonstrated on Rab11a. This suggests a new pathway whereby a cargo protein, such as a Gprotein-coupled receptor, can regulate its own trafficking by inducing the ubiquitylation and activation of a Rab GTPase.

Original languageEnglish
Pages (from-to)111-123
Number of pages13
JournalJournal of Cell Science
Volume127
Issue number1
DOIs
StatePublished - 1 Jan 2014
Externally publishedYes

Keywords

  • G-protein-coupled receptor
  • Gpcr
  • Rab
  • Trafficking

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