Oxidation of cofilin mediates T cell hyporesponsiveness under oxidative stress conditions.
Oxidative stress leads to impaired T cell activation. A central integrator of T cell activation is the actin-remodelling protein cofilin. Cofilin is activated through dephosphorylation at Ser3. Activated cofilin enables actin dynamics through severing and depolymerization of F-actin. Binding of cofilin to actin is required for formation of the immune synapse and T cell activation. Here, we showed that oxidatively stressed human T cells were impaired in chemotaxis- and costimulation-induced F-actin modulation. Although cofilin was dephosphorylated, steady-state F-actin levels increased under oxidative stress conditions. Mass spectrometry revealed that cofilin itself was a target for oxidation. Cofilin oxidation induced formation of an intramolecular disulfide bridge and loss of its Ser3 phosphorylation. Importantly, dephosphorylated oxidized cofilin, although still able to bind to F-actin, did not mediate F-actin depolymerization. Impairing actin dynamics through oxidation of cofilin provides a molecular explanation for the T cell hyporesponsiveness caused by oxidative stress.
Klemke
Martin
M
Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
Wabnitz
Guido H
GH
Funke
Faustina
F
Funk
Beate
B
Kirchgessner
Henning
H
Samstag
Yvonne
Y
D051339:Actin Depolymerizing Factors / Q000737:chemistry / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D054461:Lim Kinases / Q000378:metabolism; D008213:Lymphocyte Activation; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D051339:Actin Depolymerizing Factors; D000199:Actins; D018106:CD28 Antigens; D017252:CD3 Complex; D006861:Hydrogen Peroxide; D054461:Lim Kinases