Psoralen and Ultraviolet A Light Treatment Directly Affects Phosphatidylinositol 3-Kinase Signal Transduction by Altering Plasma Membrane Packing

• Published in: The Journal of biological chemistry 2016-11, Vol.291 (47), p.24364-24376
• Main Authors: Van Aelst, Britt, Devloo, Rosalie, Zachée, Pierre, t'Kindt, Ruben, Sandra, Koen, Vandekerckhove, Philippe, Compernolle, Veerle, Feys, Hendrik B.
• Format: Article
• Language: English
• Subjects: Agammaglobulinaemia Tyrosine Kinase; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Cell Biology; Cell Membrane - enzymology; Cell Membrane - pathology; Female; Ficusin - pharmacology; Graft vs Host Disease - drug therapy; Graft vs Host Disease - metabolism; Humans; Male; membrane lipid; phosphatidylinositide 3-kinase (PI 3-kinase); Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol Phosphates - genetics; Phosphatidylinositol Phosphates - metabolism; photobiology; plasma membrane; platelet; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; psoralen; PUVA Therapy; signal transduction; Signal Transduction - drug effects; Signal Transduction - radiation effects; T-Lymphocytes - enzymology; Ultraviolet Rays
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.735126

Psoralen and ultraviolet A light (PUVA) are used to kill pathogens in blood products and as a treatment of aberrant cell proliferation in dermatitis, cutaneous T-cell lymphoma, and graft-versus-host disease. DNA damage is well described, but the direct effects of PUVA on cell signal transduction are poorly understood. Because platelets are anucleate and contain archetypal signal transduction machinery, they are ideally suited to address this. Lipidomics on platelet membrane extracts showed that psoralen forms adducts with unsaturated carbon bonds of fatty acyls in all major phospholipid classes after PUVA. Such adducts increased lipid packing as measured by a blue shift of an environment-sensitive fluorescent probe in model liposomes. Furthermore, the interaction of these liposomes with lipid order-sensitive proteins like amphipathic lipid-packing sensor and α-synuclein was inhibited by PUVA. In platelets, PUVA caused poor membrane binding of Akt and Bruton's tyrosine kinase effectors following activation of the collagen glycoprotein VI and thrombin protease-activated receptor (PAR) 1. This resulted in defective Akt phosphorylation despite unaltered phosphatidylinositol 3,4,5-trisphosphate levels. Downstream integrin activation was furthermore affected similarly by PUVA following PAR1 (effective half-maximal concentration (EC50), 8.4 ± 1.1 versus 4.3 ± 1.1 μm) and glycoprotein VI (EC50, 1.61 ± 0.85 versus 0.26 ± 0.21 μg/ml) but not PAR4 (EC50, 50 ± 1 versus 58 ± 1 μm) signal transduction. Our findings were confirmed in T-cells from graft-versus-host disease patients treated with extracorporeal photopheresis, a form of systemic PUVA. In conclusion, PUVA increases the order of lipid phases by covalent modification of phospholipids, thereby inhibiting membrane recruitment of effector kinases.