Cells secrete into the extracellular medium vesicles of different size and origin whose cargoes (lipids, proteins, nucleic acids) can be used by recipient cells. The major role that extracellular vesicles (EVs) play in normal or pathological intercellular communication explains the enormous interest that they have generated in recent years. For example, EVs are particularly studied in the context of cancer and metastasis processes or the propagation of pathogens within the nervous system. It is also thought that they could soon be modified to carry therapeutic molecules to diseased cells. In spite of this considerable interest, the mechanisms by which vesicles are specifically bound to target cells and how biological material is released into them are still not known.
Our team has been interested for many years in endosomal trafficking, the genesis and fate of a subclass of EVs that originate in endosomes and are called exosomes. In this context, we are particularly interested in the Alix protein which is involved in both the genesis of exosomes and their fusion to endosomal membranes. Moreover, this protein plays a central role in membrane reorganization and fission necessary for many cellular processes ranging from cytokinesis to membrane repair, enveloped virus formation and endocytosis, as we have shown more recently. Alix is able to associate and organize ESCRT complexes but also endophilins, two classes of proteins also involved in membrane fission.
The goal of our current research is to better define the effect of Alix binding to membranes on their fusion capabilities in the presence or absence of accessory proteins. For this purpose we are using mainly cultured cells and artificial membranes. We also seek to define the structure of different forms of Alix whose conformational changes seem essential to its function. Finally, we use Alix as a common thread in the search for the molecular mechanisms that allow exosomes to release their biological material into recipient cells.
Alix is required for activity-dependent bulk endocytosis at brain synapses.
Laporte MH, Chi KI, Caudal LC, Zhao N, Schwarz Y, Rolland M, Martinez-Hernandez J, Martineau M, Chatellard C, Denarier E, Mercier V, Lemaître F, Blot B, Moutaux E, Cazorla M, Perrais D, Lanté F, Bruns D, Fraboulet S, Hemming FJ, Kirchhoff F, Sadoul R.
PLoS Biol. 2022, 20(6):e3001659
Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons.
Laulagnier K, Javalet C, Hemming FJ, Chivet M, Lachenal G, Blot B, Chatellard C, Sadoul R.
Cell Mol Life Sci. 2018, 75(4):757.
Laulagnier K, Javalet C, Hemming FJ, Sadoul R.
Purification and Analysis of Exosomes Released by Mature Cortical Neurons Following Synaptic Activation. Methods Mol Biol. 2017,1545:129.
Alix is required during development for normal growth of the mouse brain.
Laporte MH, Chatellard C, Vauchez V, Hemming FJ, Deloulme JC, Vossier F, Blot B, Fraboulet S, Sadoul R.
Sci Rep. 2017 7:44767.
ALG-2 interacting protein-X (Alix) is essential for clathrin-independent endocytosis and signaling.
Mercier V, Laporte MH, Destaing O, Blot B, Blouin CM, Pernet-Gallay K, Chatellard C, Saoudi Y, Albiges-Rizo C, Lamaze C, Fraboulet S, Petiot A, Sadoul R.
Sci Rep. 2016, 6:26986.
Exosomes secreted by cortical neurons upon glutamatergic synapse activation specifically interact with neurons.
Chivet M, Javalet C, Laulagnier K, Blot B, Hemming FJ, Sadoul R.
J Extracell Vesicles. 2014, 3:24722.
Exosomes as a novel way of interneuronal communication.
Chivet M, Javalet C, Hemming F, Pernet-Gallay K, Laulagnier K, Fraboulet S, Sadoul R.
Biochem Soc Trans. 2013, 41(1):241.