Dynamic regulation of neutrophil survival through tyrosine phosphorylation or dephosphorylation of caspase-8
Dynamic regulation of neutrophil survival through tyrosine phosphorylation or dephosphorylation of caspase-8
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DOI：
10.1074/jbc.m706462200
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发表时间：
2008-02-29
影响因子：
4.8
通讯作者：
Marshall, John C.
中科院分区：
文献类型：
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作者：
Jia, Song Hui;Parodo, Jean;Marshall, John C.
先天免疫的有效表达在很大程度上取决于中性粒细胞在面临急性威胁时迅速激活并在威胁消除后重新激活的能力。在这里，我们报告了一种通过酪氨酸磷酸化或去磷酸化caspase-8动态调节中性粒细胞存活的新机制。Caspase-8在新分离的中性粒细胞中酪氨酸磷酸化，但在培养中自发去磷酸化，与组成性凋亡的进展有关。Tyr-310上caspase-8的磷酸化促进了其与含有酪氨酸磷酸酶-1 （SHP-1）的src同源结构域2的相互作用，并使SHP-1去磷酸化caspase-8，从而允许细胞凋亡进行。非受体酪氨酸激酶Lyn可以磷酸化酪氨酸- 397和酪氨酸-465上的caspase-8，使其抵抗活化裂解并抑制细胞凋亡。暴露于脂多糖会降低SHP-1活性、与caspase-8的结合、caspase-8活性和自发凋亡率。脓毒症患者中性粒细胞中SHP-1活性降低，Lyn升高，与深度延迟的细胞凋亡有关；抑制Lyn可以部分逆转这种延迟。因此，分别由Lyn和SHP-1介导的caspase-8的磷酸化和去磷酸化代表了一种新的、动态的翻译后中性粒细胞凋亡调节机制，其失调有助于脓毒症中中性粒细胞的持续存活。
Efficient expression of innate immunity is critically dependent upon the capacity of the neutrophil to be activated rapidly in the face of an acute threat and to involute once that threat has been eliminated. Here we report a novel mechanism regulating neutrophil survival dynamically through the tyrosine phosphorylation or dephosphorylation of caspase-8. Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr- 397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis. SHP-1 activity is reduced and Lyn increased in neutrophils from patients with sepsis, in association with profoundly delayed apoptosis; inhibition of Lyn can partially reverse this delay. Thus the phosphorylation and dephosphorylation of caspase-8, mediated by Lyn and SHP-1, respectively, represents a novel, dynamic post-translational mechanism for the regulation of neutrophil apoptosis whose dysregulation contributes to persistent neutrophil survival in sepsis.