Redox regulation of 14-3-3ζ controls monocyte migration.
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.


APPROACH AND 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.
['Kim|Hong Seok|HS|', 'Ullevig|Sarah L|SL|', 'Nguyen|Huynh Nga|HN|', 'Vanegas|Difernando|D|', 'Asmis|Reto|R|']
D048948:14-3-3 Proteins D051339:Actin Depolymerizing Factors D000818:Animals D050197:Atherosclerosis D018932:Chemokine CCL2 D002634:Chemotaxis, Leukocyte D004195:Disease Models, Animal D005947:Glucose D054477:Glutaredoxins D005978:Glutathione D057809:HEK293 Cells D006801:Humans D054461:Lim Kinases D008077:Lipoproteins, LDL D008297:Male D051379:Mice D018345:Mice, Knockout D009000:Monocytes D009154:Mutation D010084:Oxidation-Reduction D018384:Oxidative Stress D010641:Phenotype D010749:Phosphoprotein Phosphatases D010766:Phosphorylation D059748:Proteolysis D011973:Receptors, LDL D013997:Time Factors D014162:Transfection
monocyte migration atherosclerosis metabolic disorder oxidation-reduction