title: Redox regulation of 14-3-3ζ controls monocyte migration.
abstract: OBJECTIVE
  Metabolic stress primes monocytes for accelerated chemokine-mediated adhesion, migration, and recruitment into vascular lesions by increasing actin remodeling. The mechanism linking metabolic stress to accelerated actin turnover and enhanced monocyte migration was not known. We tested the hypothesis that in metabolically primed monocytes, the acceleration of monocyte chemoattractant protein-1-induced chemotaxis is mediated by the hyperactivation of cofilin.
  
  
  RESULTS
  Metabolic priming was induced by exposing human THP-1 monocytes to diabetic conditions, that is, human native low-density lipoprotein plus high glucose concentrations. In healthy monocytes, monocyte chemoattractant protein-1 induced the phosphorylation and inactivation of cofilin. This response was completely blocked in metabolically primed monocytes but restored by overexpression of the thiol transferase, glutaredoxin 1. Cofilin kinase, LIM kinase 1, and cofilin phosphatase, Slingshot-1L, were not affected by metabolic stress. However, metabolic priming increased 3.8-fold the S-glutathionylation of the Slingshot-1L-binding protein 14-3-3ζ (zeta), resulting in its caspase-dependent degradation. Glutaredoxin 1 overexpression inhibited low-density lipoprotein plus high glucose-induced S-glutathionylation and degradation of 14-3-3ζ. The C25S mutant of 14-3-3ζ was resistant to both S-glutathionylation and degradation induced by low-density lipoprotein plus high glucose. Overexpression of the C25S mutant restored monocyte chemoattractant protein-1-induced cofilin phosphorylation and prevented accelerated migration of metabolically stressed monocytes, suggesting that loss of 14-3-3ζ increases the pool of free Slingshot-1L phosphatase, thereby preventing the phosphorylation and deactivation of cofilin in response to chemokine activation.
  
  
  CONCLUSIONS
  By preventing the inactivation of cofilin, metabolic stress-induced degradation of 14-3-3ζ promotes the conversion of blood monocytes into a hypermigratory, proatherogenic phenotype.
authors.affiliation: From the Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio (H.S.K., D.V., R.A.); Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio (S.L.U.); and Department of Biochemistry, University of Texas Health Science Center at San Antonio (H.N.N., R.A.).
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: From the Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio (H.S.K., D.V., R.A.); Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio (S.L.U.); and Department of Biochemistry, University of Texas Health Science Center at San Antonio (H.N.N., R.A.).
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Ullevig
authors.affiliation: From the Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio (H.S.K., D.V., R.A.); Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio (S.L.U.); and Department of Biochemistry, University of Texas Health Science Center at San Antonio (H.N.N., R.A.).
authors.forename: Huynh Nga
authors.initials: HN
authors.lastname: Nguyen
authors.affiliation: From the Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio (H.S.K., D.V., R.A.); Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio (S.L.U.); and Department of Biochemistry, University of Texas Health Science Center at San Antonio (H.N.N., R.A.).
authors.forename: Difernando
authors.initials: D
authors.lastname: Vanegas
authors.affiliation: From the Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio (H.S.K., D.V., R.A.); Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio (S.L.U.); and Department of Biochemistry, University of Texas Health Science Center at San Antonio (H.N.N., R.A.). asmis@uthscsa.edu.
authors.forename: Reto
authors.initials: R
authors.lastname: Asmis
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D054477:Glutaredoxins / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism*; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D059748:Proteolysis; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D014162:Transfection
chemical_list: D048948:14-3-3 Proteins; D051339:Actin Depolymerizing Factors; D018932:Chemokine CCL2; D005947:Glucose; D054477:Glutaredoxins; D005978:Glutathione; D054461:Lim Kinases; D008077:Lipoproteins, LDL; D010749:Phosphoprotein Phosphatases; D011973:Receptors, LDL; C000590975:Ywhaz protein, mouse; C111835:CCL2 protein, human; C516005:GLRX protein, human; C572235:YWHAZ protein, human; C515892:LIMK1 protein, human; C484329:SSH1 protein, human
keywords: atherosclerosis; metabolic disorder; migration; monocyte; oxidation-reduction