title: S-Glutathionylation of Keap1: a new role for glutathione S-transferase pi in neuronal protection.
abstract: Oxidative stress is a key pathological feature of Parkinson's disease (PD). Glutathione S-transferase pi (GSTP) is a neuroprotective antioxidant enzyme regulated at the transcriptional level by the antioxidant master regulator nuclear factor-erythroid 2-related factor 2 (Nrf2). Here, we show for the first time that upon MPTP-induced oxidative stress, GSTP potentiates S-glutathionylation of Kelch-like ECH-associated protein 1 (Keap1), an endogenous repressor of Nrf2, in vivo. S-glutathionylation of Keap1 leads to Nrf2 activation and subsequently increases expression of GSTP. This positive feedback regulatory loop represents a novel mechanism by which GSTP elicits antioxidant protection in the brain.
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors.forename: Andreia Neves
authors.initials: AN
authors.lastname: Carvalho
authors.affiliation: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Marques
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.|Department of Pharmaceutical Chemistry and Therapeutics, Faculty of Pharmacy, University of Lisbon, Portugal.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.|Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Castro-Caldas
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.|Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Portugal.
authors.forename: Elsa
authors.initials: E
authors.lastname: Rodrigues
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.|Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Portugal.
authors.forename: Maria João
authors.identifier: 0000-0002-4943-0349
authors.initials: MJ
authors.lastname: Gama
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D051267:NF-E2-Related Factor 2 / Q000737:chemistry / Q000378:metabolism*; D018384:Oxidative Stress; D011485:Protein Binding
chemical_list: C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051549:Glutathione S-Transferase pi; C496557:Gstp1 protein, mouse; D005978:Glutathione
keywords: Glutathione S-Transferase pi; Nrf2-Keap1 pathway; S-glutathionylation