Psoralen and Ultraviolet A Light Treatment Directly Affects Phosphatidylinositol 3-Kinase Signal Transduction by Altering Plasma Membrane Packing.
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.
From the Transfusion Research Center, Belgian Red Cross-Flanders, 9000 Ghent, Belgium.
Britt
B
Van Aelst
From the Transfusion Research Center, Belgian Red Cross-Flanders, 9000 Ghent, Belgium.
Rosalie
R
Devloo
the Department of Hematology, Hospital Network Antwerp, 2000 Antwerp, Belgium.
Pierre
P
Zachée
the Research Institute for Chromatography, 8500 Kortrijk, Belgium.
Ruben
R
t'Kindt
the Research Institute for Chromatography, 8500 Kortrijk, Belgium.
Koen
K
Sandra
the Blood Service of the Belgian Red Cross-Flanders, 2800 Mechelen, Belgium,; the Department of Public Health and Primary Care, KULeuven, 3000 Leuven, Belgium, and; the Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
Philippe
P
Vandekerckhove
From the Transfusion Research Center, Belgian Red Cross-Flanders, 9000 Ghent, Belgium,; the Blood Service of the Belgian Red Cross-Flanders, 2800 Mechelen, Belgium,; the Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
Veerle
V
Compernolle
From the Transfusion Research Center, Belgian Red Cross-Flanders, 9000 Ghent, Belgium,. Electronic address: hendrik.feys@rodekruis.be.
Hendrik B
HB
Feys
D000077329:Agammaglobulinaemia Tyrosine Kinase; D002462:Cell Membrane / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005363:Ficusin / Q000494:pharmacology*; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D011701:PUVA Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013601:T-Lymphocytes / Q000201:enzymology*; D014466:Ultraviolet Rays; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D018129:Phosphatidylinositol Phosphates; C497604:SNCA protein, human; D051844:alpha-Synuclein; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D051057:Proto-Oncogene Proteins c-akt; D005363:Ficusin
membrane lipid; phosphatidylinositide 3-kinase (PI 3-kinase); photobiology; plasma membrane; platelet; psoralen; signal transduction
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