Redox regulation of 14-3-3ζ controls monocyte migration.
Redox regulation of 14-3-3ζ controls monocyte migration.
复制标题
14-3-3ζ的氧化还原调节控制单核细胞迁移。
DOI：
10.1161/atvbaha.114.303746
复制
发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Asmis R
中科院分区：
文献类型：
--
作者：
Kim HS;Ullevig SL;Nguyen HN;Vanegas D;Asmis R
代谢应激通过增加肌动蛋白重塑使单核细胞加速趋化因子介导的粘附、迁移和募集到血管病变中。代谢应激与肌动蛋白更新加速和单核细胞迁移增强的机制尚不清楚。我们测试了这样的假设，即在代谢启动的单核细胞中，MCP-1诱导的趋化性的加速是由cofilin的超活化介导的。通过将人THP-1单核细胞暴露于糖尿病条件，即人天然LDL加高葡萄糖浓度（LDL+HG）来诱导代谢引发。在健康单核细胞中，MCP-1诱导cofilin的磷酸化和失活。这种反应在代谢启动的单核细胞中被完全阻断，但通过巯基转移酶谷氧还蛋白1（Grx 1）的过度表达而恢复。Cofilin激酶LIMK 1和Cofilin磷酸酶SSH 1 L不受代谢应激的影响。然而，代谢引发增加了3.8倍的SSH 1 L结合蛋白14-3- 3 zeta的S-谷胱甘肽化，导致其半胱天冬酶依赖性降解。Grx 1过表达抑制LDL+ HG诱导的S-谷胱甘肽化和14-3- 3 zeta降解。14-3- 3 zeta的C25 S突变体对LDL+HG诱导的S-谷胱甘肽化和降解均具有抗性。C25 S突变体的过表达恢复了MCP-1诱导的cofilin磷酸化，并阻止了代谢应激单核细胞的加速迁移，这表明14-3- 3 zeta的缺失增加了游离SSH 1 L磷酸酶的库，从而阻止了响应于趋化因子激活的cofilin的磷酸化和失活。通过阻止cofilin的失活，代谢应激诱导的14-3- 3 zeta降解促进血液单核细胞转化为超迁移的致动脉粥样硬化表型。
Metabolic stress primes monocytes for accelerated chemokine-mediated adhesion, migration and recruitment into vasculature 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 MCP-1-induced chemotaxis is mediated by the hyper-activation of cofilin. Metabolic priming was induced by exposing human THP-1 monocytes to diabetic conditions, i.e. human native LDL plus high glucose concentrations (LDL+HG). In healthy monocytes, MCP-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 (Grx1). Cofilin kinase, LIMK1, and cofilin phosphatase, SSH1L, were not affected by metabolic stress. However, metabolic priming increased 3.8-fold the S-glutathionylation of the SSH1L-binding protein 14-3-3zeta, resulting in its caspase-dependent degradation. Grx1 overexpression inhibited LDL+HG-induced S-glutathionylation and degradation of 14-3-3zeta. The C25S mutant of 14-3-3zeta was resistant to both S-glutathionylation and degradation induced by LDL+HG. Overexpression of the C25S mutant restored MCP-1-induced cofilin phosphorylation and prevented accelerated migration of metabolically stressed monocytes, suggesting that loss of 14-3-3zeta increases the pool of free SSH1L phosphatase, thereby preventing the phosphorylation and deactivation of cofilin in response to chemokine activation. By preventing the inactivation of cofilin, metabolic stress-induced degradation of 14-3-3zeta promotes the conversion of blood monocytes into a hyper-migratory, proatherogenic phenotype.