Ubiquitin and Trafficking

The secretory pathway mediates the targeting of a number of proteins from the site where they synthesize, the endoplasmic reticulum (ER), towards various other intracellular organelles, the plasma membrane and the extracellular medium. The budding yeast S. cerevisiae has long been a powerful tool for understanding intracellular traffic along this pathway.

The endocytic pathway mediates the uptake of small nutrients and the internalization of plasma membrane receptors or transporters for signalling functions or downregulation. The use of S. cerevisiae as a model eukaryote to elucidate the mechanisms involved in the corresponding trafficking routes has emphasized the role played by ubiquitylation events at several stages of the endocytic pathway. Importantly, this role involves ubiquitylation functions that are distinct from those leading to proteasome degradation. We have largely contributed to these latter studies, on which we have focused our attention for the last few years. We were one of the first groups to discover that the main internalization signal in yeast is the modification of target plasma membrane proteins by covalent addition of ubiquitin. This modification, mediated by the ubiquitin protein ligase Rsp5, is triggered by the addition of ligands, in the case of receptors, or substrates and various nutrients, in the case of transporters. Human homologues of Rsp5 are involved in ubiquitin-dependent endocytosis of various receptors, channels or transporters. For instance, the Liddle syndrome, a severe form of hypertension, results from a deficiency in the ubiquitylation, by one of these homologues, of the sodium channel ENaC.

    We have demonstrated that Rsp5 is not only involved in ubiquitin-dependent internalization of plasma membrane proteins, it also plays a role in ubiquitylation leading to sorting to internal vesicles of the multivesicular body (MVB), a key endosomal compartment. Strikingly, some viruses, including HIV1 in human, hijack the ubiquitylation enzymes and the host MVB-sorting machinery to drive viral budding at the plasma membrane. 

    Now that the complete yeast genome sequence has become available, genomic approaches are reinforcing genetic studies in S. cerevisiae. We have contributed, within the framework of the European project EUROFAN, to the identification of the orphan genes involved in intracellular trafficking along the secretory and endocytic pathways, and we have identified genes, conserved from yeast to man, that are involved in the Golgi to ER retrograde pathway, Golgi to vacuole/lysosome trafficking and recycling from endosomes back to the plasma membrane.

 

Selection of Publications

Erpapazoglou Z, Dhaoui M, Pantazopoulou M, Giordano F, Mari M, Léon S, Raposo G, Reggiori F, Haguenauer-Tsapis R.
A dual role for K63-linked ubiquitin chains in multivesicular bodies biogenesis and cargo sorting.
Mol Biol Cell. 2012 Apr 11. [Epub ahead of print]
Abstract

Becuwe M, Vieira N, Lara D, Gomes-Rezende J, Soares-Cunha C, Casal M, Haguenauer-Tsapis R, Vincent O, Paiva S, Léon S.
A molecular switch on an arrestin-like protein relays glucose signaling to transporter endocytosis.
J Cell Biol. 2012 Jan 16;196(2): 247-259.
Abstract
In Focus in JCB, January 16, 2012

Paiva S, Vieira N, Nondier I, Haguenauer-Tsapis R, Casal M, Urban-Grimal D.
Glucose-induced ubiquitylation and endocytosis of the yeast Jen1 transporter: role of lysine 63-linked ubiquitin chains.
J Biol Chem. 2009 Jul 17;284(29):19228-36.
Abstract

Léon S, Erpapazoglou Z, Haguenauer-Tsapis R.
Ear1p and Ssh4p are new adaptors of the ubiquitin ligase Rsp5p for cargo ubiquitylation and sorting at multivesicular bodies.
Mol Biol Cell. 2008 Jun;19(6):2379-88. Epub 2008 Mar 26.
Abstract

Galan JM, Haguenauer-Tsapis R.
Ubiquitin lys63 is involved in ubiquitination of a yeast plasma membrane protein.
EMBO J . 1997 Oct 1;16(19):5847-54.
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Last modified 04/23/2012

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