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Psoralen and ultraviolet A light treatment directly affects phosphatidylinositol 3-kinase signal transduction by altering plasma membrane packing

(2016) JOURNAL OF BIOLOGICAL CHEMISTRY. 291(47). p.24364-24376
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Abstract
Psoralen and ultraviolet A light (PUNTA) 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 a-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 (EC), 8.4 +/- 1.1 versus 4.3 +/- 1.1 mu M) and glycoprotein VI (EC50, 1.61 +/- 0.85 versus 0.26 +/- 0.21 mu g/ml) but not PAR4 (EC50, 50 +/- 1 versus 58 +/- 1 mu m) signal transduction. Our findings were confirmed in T-cells ftom 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.
Keywords
PLATELET ACTIVATION, LIPID PACKING, EXTRACORPOREAL PHOTOPHERESIS, PHOTOCHEMICAL INACTIVATION, IMMUNE SUPPRESSION, THROMBUS FORMATION, MASS-SPECTROMETRY, NUCLEIC-ACID, PUVA THERAPY, IN-VITRO

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Chicago
Van Aelst, Britt, Rosalie Devloo, Pierre Zachée, Ruben t’ Kindt, Koen Sandra, Philippe Vandekerckhove, Veerle Compernolle, and Hendrik Feys. 2016. “Psoralen and Ultraviolet A Light Treatment Directly Affects Phosphatidylinositol 3-kinase Signal Transduction by Altering Plasma Membrane Packing.” Journal of Biological Chemistry 291 (47): 24364–24376.
APA
Van Aelst, Britt, Devloo, R., Zachée, P., t’ Kindt, R., Sandra, K., Vandekerckhove, P., Compernolle, V., et al. (2016). Psoralen and ultraviolet A light treatment directly affects phosphatidylinositol 3-kinase signal transduction by altering plasma membrane packing. JOURNAL OF BIOLOGICAL CHEMISTRY, 291(47), 24364–24376.
Vancouver
1.
Van Aelst B, Devloo R, Zachée P, t’ Kindt R, Sandra K, Vandekerckhove P, et al. Psoralen and ultraviolet A light treatment directly affects phosphatidylinositol 3-kinase signal transduction by altering plasma membrane packing. JOURNAL OF BIOLOGICAL CHEMISTRY. 2016;291(47):24364–76.
MLA
Van Aelst, Britt, Rosalie Devloo, Pierre Zachée, et al. “Psoralen and Ultraviolet A Light Treatment Directly Affects Phosphatidylinositol 3-kinase Signal Transduction by Altering Plasma Membrane Packing.” JOURNAL OF BIOLOGICAL CHEMISTRY 291.47 (2016): 24364–24376. Print.
@article{8507045,
  abstract     = {Psoralen and ultraviolet A light (PUNTA) 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 a-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 (EC), 8.4 +/- 1.1 versus 4.3 +/- 1.1 mu M) and glycoprotein VI (EC50, 1.61 +/- 0.85 versus 0.26 +/- 0.21 mu g/ml) but not PAR4 (EC50, 50 +/- 1 versus 58 +/- 1 mu m) signal transduction. Our findings were confirmed in T-cells ftom 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.},
  author       = {Van Aelst, Britt and Devloo, Rosalie and Zach{\'e}e, Pierre and t'Kindt, Ruben and Sandra, Koen and Vandekerckhove, Philippe and Compernolle, Veerle and Feys, Hendrik},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  language     = {eng},
  number       = {47},
  pages        = {24364--24376},
  title        = {Psoralen and ultraviolet A light treatment directly affects phosphatidylinositol 3-kinase signal transduction by altering plasma membrane packing},
  url          = {http://dx.doi.org/10.1074/jbc.m116.735126},
  volume       = {291},
  year         = {2016},
}

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