title: Protein disulfide isomerases: Redox connections in and out of the endoplasmic reticulum.
abstract: Protein disulfide isomerases are thiol oxidoreductase chaperones from thioredoxin superfamily. As redox folding catalysts from the endoplasmic reticulum (ER), their roles in ER-related redox homeostasis and signaling are well-studied. PDIA1 exerts thiol oxidation/reduction and isomerization, plus chaperone effects. Also, substantial evidence indicates that PDIs regulate thiol-disulfide switches in other cell locations such as cell surface and possibly cytosol. Subcellular PDI translocation routes remain unclear and seem Golgi-independent. The list of signaling and structural proteins reportedly regulated by PDIs keeps growing, via thiol switches involving oxidation, reduction and isomerization, S-(de)nytrosylation, (de)glutathyonylation and protein oligomerization. PDIA1 is required for agonist-triggered Nox NADPH oxidase activation and cell migration in vascular cells and macrophages, while PDIA1-dependent cytoskeletal regulation appears a converging pathway. Extracellularly, PDIs crucially regulate thiol redox signaling of thrombosis/platelet activation, e.g., integrins, and PDIA1 supports expansive caliber remodeling during injury repair via matrix/cytoskeletal organization. Some proteins display regulatory PDI-like motifs. PDI effects are orchestrated by expression levels or post-translational modifications. PDI is redox-sensitive, although probably not a mass-effect redox sensor due to kinetic constraints. Rather, the "all-in-one" organization of its peculiar redox/chaperone properties likely provide PDIs with precision and versatility in redox signaling, making them promising therapeutic targets.
authors.affiliation: Vascular Biology Laboratory, Heart Institute (InCor), University of São Paulo, School of Medicine, São Paulo, Brazil.
authors.forename: Ana Iochabel
authors.initials: AI
authors.lastname: Soares Moretti
authors.affiliation: Vascular Biology Laboratory, Heart Institute (InCor), University of São Paulo, School of Medicine, São Paulo, Brazil. Electronic address: francisco.laurindo@incor.usp.br.
authors.forename: Francisco Rafael
authors.initials: FR
authors.lastname: Martins Laurindo
mesh_terms: D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D010545:Peroxides / Q000737:chemistry; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: D004220:Disulfides; D018832:Molecular Chaperones; D010545:Peroxides; D011393:Procollagen-Proline Dioxygenase; D019255:NADPH Oxidases; C526497:P4HB protein, human; D019704:Protein Disulfide-Isomerases
keywords: Endoplasmic reticulum; Endothelial cells; Protein disulfide isomerase; Redox signaling; Thiol proteins; Thrombosis