title: Plasminogen activator inhibitor 1 is an intracellular inhibitor of furin proprotein convertase.
abstract: Proprotein convertases (PCs) are a family of serine proteases that are involved in the post-translational processing and activation of a wide range of regulatory proteins. The upstream role of PCs in the control of many physiological and pathological processes generates a growing interest in understanding their regulation. Here, we demonstrate that the serine protease inhibitor plasminogen activator inhibitor 1 (PAI-1) forms an SDS-stable complex with the PC furin, which leads to the inhibition of the intra-Golgi activity of furin. It is known that elevated PAI-1 plasma levels are correlated with the occurrence of the metabolic syndrome and type 2 diabetes, and we show that PAI-1 reduces the furin-dependent maturation and activity of the insulin receptor and ADAM17: two proteins involved in the onset of these metabolic disorders. In addition to demonstrating that PAI-1 is an intracellular inhibitor of furin, this study also provides arguments in favor of an active role for PAI-1 in the development of metabolic disorders.
authors.affiliation: Inserm, U626, Université de Méditerranée, Faculté de Médecine, 27 Boulevard Jean Moulin, 13385 Marseilles Cedex 5, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Bernot
authors.forename: Jimmy
authors.initials: J
authors.lastname: Stalin
authors.forename: Pierre
authors.initials: P
authors.lastname: Stocker
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bonardo
authors.forename: Ilse
authors.initials: I
authors.lastname: Scroyen
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Alessi
authors.forename: Franck
authors.initials: F
authors.lastname: Peiretti
mesh_terms: D002460:Cell Line; D004791:Enzyme Inhibitors / Q000378:metabolism*; D045683:Furin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational
chemical_list: D004791:Enzyme Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D045683:Furin