title: UVA1 radiation inhibits calcineurin through oxidative damage mediated by photosensitization.
abstract: The protein phosphatase calcineurin has been gradually revealing itself as the central controller of our immune response, although it is involved in a wide array of signaling pathways related to cellular development and cell cycle progression. As such, calcineurin is an attractive, yet delicate, therapeutic target for the prevention of allograft rejection and treatment of several inflammatory skin conditions. However, calcineurin activity is not only sensitive to immunosuppressants such as cyclosporin A and tacrolimus, but also subject to modulation by reactive oxygen species. We have recently shown, both in vivo and in vitro, that UVA1 radiation suppresses calcineurin activity. In this paper, we present evidence that this activity loss is due to singlet oxygen and superoxide generated by photosensitization and show that a closely related phosphatase, PP2A, is not affected. Furthermore, a survey of this damage reveals oxidation of several Met and Cys residues as well as an overall conformational change. These findings provide a mechanistic basis for the hypothesis that UVA1 and calcineurin inhibitors both affect the same signal transduction pathway in skin.
authors.affiliation: Department of Clinical Chemistry, Leiden University Medical Center, Leiden, The Netherlands. r.e.a.musson@lumc.nl
authors.forename: Ruben E A
authors.initials: RE
authors.lastname: Musson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hensbergen
authors.forename: Adrie H
authors.initials: AH
authors.lastname: Westphal
authors.forename: Wouter P M
authors.initials: WP
authors.lastname: Temmink
authors.forename: André M
authors.initials: AM
authors.lastname: Deelder
authors.forename: Johannes
authors.initials: J
authors.lastname: van Pelt
authors.forename: Leon H F
authors.initials: LH
authors.lastname: Mullenders
authors.forename: Nico P M
authors.initials: NP
authors.lastname: Smit
mesh_terms: D019703:Calcineurin / Q000737:chemistry / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011487:Protein Conformation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D026082:Singlet Oxygen / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D013481:Superoxides; D026082:Singlet Oxygen; D019703:Calcineurin