Les phosphoinositides, des lipides acteurs essentiels du trafic intracellulaire

Phosphoinositides: lipidic essential actors in the intracellular traffic

Département de Génétique Moléculaire et Cellulaire, UMR 7156, Université de Strasbourg et CNRS, 67084 Strasbourg, France

Auteur correspondant : Sylvie Friant, s.friant@unistra.fr

Reçu : 19 Novembre 2014

Résumé

Les phosphoinositides sont des lipides impliqués dans le transport vésiculaire des protéines entre les différents compartiments. Ils agissent par le recrutement et/ou l’activation de protéines effectrices et sont de ce fait impliqués dans la régulation de différentes fonctions cellulaires telles que le bourgeonnement vésiculaire, la fusion ou la dynamique des membranes et du cytosquelette. Bien que présents en faible concentration dans les membranes, leur rôle est indispensable à la survie des cellules et doit être régulé avec précision. Le contrôle de leur fonction se fait par la phosphorylation/déphosphorylation des positions D3, D4 et/ou D5 de leur anneau inositol par des kinases et phosphatases spécifiques des différentes membranes intracellulaires. Ces enzymes sont en partie conservées entre la levure et l’Homme et leur perte de fonction peut entraîner des maladies génétiques graves comme les myopathies.

Abstract

Phosphoinositides (PPIn) are lipids involved in the vesicular transport of proteins between the different intracellular compartments. They act by recruiting and/or activating effector proteins and are thus involved in crucial cellular functions including vesicle budding, fusion and dynamics of membranes and regulation of the cytoskeleton. Although they are present in low concentrations in membranes, their activity is essential for cell survival and needs to be tightly controlled. Therefore, phosphatases and kinases specific of the various cellular membranes can phosphorylate/dephosphorylate their inositol ring on the positions D3, D4 and/or D5. The differential phosphorylation determines the intracellular localisation and the activity of the PPIn. Indeed, non-phosphorylated phosphatidylinositol (PtdIns) is the basic component of the PPIn and can be found in all eukaryotic cells at the cytoplasmic face of the ER, the Golgi, mitochondria and microsomes. It can get phosphorylated on position D4 to obtain PtdIns4P, a PPIn enriched in the Golgi compartment and involved in the maintenance of this organelle as well as anterograde and retrograde transport to and from the Golgi. PtdIns phosphorylation on position D3 results in PtdIns3P that is required for endosomal transport and multivesicular body (MVB) formation and sorting. These monophosphorylated PtdIns can be further phosphorylated to produce bisphophorylated PtdIns. Thus, PtdIns(4,5)P₂, mainly produced by PtdIns4P phosphorylation, is enriched in the plasma membrane and involved in the regulation of actin cytoskeleton and endocytosis. PtdIns(3,5)P₂, mainly produced by PtdIns3P phosphorylation, is enriched in late endosomes, MVBs and the lysosome/vacuole and plays a role in endosome to vacuole transport. PtdIns(3,4)P₂ is absent in yeast, cells and mainly produced by PtdIns4P phosphorylation in human cells; PtdIns(3,4)P₂ is localised in the plasma membrane and plays an important role as a second messenger by recruiting specific protein kinases (Akt and PDK1). Finally the triple phosphorylated PPIn, PtdIns(3,4,5)P₃ also absent in yeast, is produced by the phosphorylation of PtdIns(3,4)P₂ and localized at the plasma membrane of human cells where it binds proteins via their PH domain. Interaction partners include members of the Arf (ADP-ribosylation factors) family, PDK1 (Phosphoinositide Dependent Kinase 1) and Akt. Therefore this last PPIn is essential for the control of cell proliferation and its deregulation leads to the development of numerous cancers. In conclusion, the regulation of PPIn phosphorylation/dephosphorylation is complex and needs to be very precisely regulated. Indeed phosphatases and kinases allow the maintenance of the equilibrium between the different forms. PPIn play a crucial role in numerous cellular functions and a loss in their synthesis or regulation results in severe genetic diseases.