The prolyl isomerase Pin1 acts as a novel molecular switch for TNF-α-induced priming of the NADPH oxidase in human neutrophils
The prolyl isomerase Pin1 acts as a novel molecular switch for TNF-α-induced priming of the NADPH oxidase in human neutrophils
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DOI：
10.1182/blood-2010-03-273094
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发表时间：
2010-12-23
期刊：
影响因子：
20.3
通讯作者：
El-Benna, Jamel
中科院分区：
文献类型：
--
作者：
Boussetta, Tarek;Gougerot-Pocidalo, Marie-Anne;El-Benna, Jamel
中性粒细胞通过释放活性氧（ROS）在宿主防御中起关键作用。然而，由嗜中性粒细胞烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶产生的过量ROS可损伤旁观者组织，从而促成炎性疾病。肿瘤坏死因子-α（TNF-α）是炎症的主要介质，不激活NADPH氧化酶，但诱导对后续刺激的高反应性状态，这种作用称为引发。TNF-α引发NADPH氧化酶的分子机制尚不清楚。在这里，我们表明，Pin 1，一个独特的顺反脯氨酰异构酶，是一个以前未被识别的调节TNF-α诱导的NADPH氧化酶超活化。我们首先发现Pin 1在中性粒细胞胞浆中表达，并且其活性被TNF-α显著增强。用胡桃醌或特异性肽抑制剂抑制Pin 1活性可消除TNF-α诱导的由N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸肽（fMLF）诱导的中性粒细胞ROS产生的启动。TNF-α增强了fMLF诱导的Pin 1和p47 phox向细胞膜的转运，而胡桃醌抑制了这一过程。Pin 1通过磷酸化的Ser 345与p47 phox结合，从而诱导构象变化，促进p47 phox通过蛋白激酶C在其他位点磷酸化。这些发现表明Pin 1对于TNF-α诱导的NADPH氧化酶引发和过量ROS产生至关重要。Pin 1抑制可能代表一种新的抗炎策略。（血。2010; 116（26）：5795-5802）
Neutrophils play a key role in host defense by releasing reactive oxygen species ( ROS). However, excessive ROS production by neutrophil nicotinamide adenine dinucleotide phosphate ( NADPH) oxidase can damage bystander tissues, thereby contributing to inflammatory diseases. Tumor necrosis factor-alpha ( TNF-alpha), a major mediator of inflammation, does not activate NADPH oxidase but induces a state of hyperresponsiveness to subsequent stimuli, an action known as priming. The molecular mechanisms by which TNF-alpha primes the NADPH oxidase are unknown. Here we show that Pin1, a unique cis-trans prolyl isomerase, is a previously unrecognized regulator of TNF-alpha-induced NADPH oxidase hyperactivation. We first showed that Pin1 is expressed in neutrophil cytosol and that its activity is markedly enhanced by TNF-alpha. Inhibition of Pin1 activity with juglone or with a specific peptide inhibitor abrogated TNF-alpha-induced priming of neutrophil ROS production induced by N-formylmethionyl-leucyl-phenylalanine peptide (fMLF). TNF-alpha enhanced fMLF-induced Pin1 and p47phox translocation to the membranes and juglone inhibited this process. Pin1 binds to p47phox via phosphorylated Ser345, thereby inducing conformational changes that facilitate p47phox phosphorylation on other sites by protein kinase C. These findings indicate that Pin1 is critical for TNF-alpha induced priming of NADPH oxidase and for excessive ROS production. Pin1 inhibition could potentially represent a novel anti-inflammatory strategy. (Blood. 2010; 116(26): 5795-5802)