A Novel Role for Plasminogen Activator Inhibitor Type-2 as a Hypochlorite-Resistant Serine Protease Inhibitor and Holdase Chaperone.
A Novel Role for Plasminogen Activator Inhibitor Type-2 as a Hypochlorite-Resistant Serine Protease Inhibitor and Holdase Chaperone.
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纤溶酶原激活物抑制剂2型作为次氯酸盐抗性丝氨酸蛋白酶抑制剂和保持酶伴侣的新作用。
DOI：
10.3390/cells11071152
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发表时间：
2022-03-29
期刊：
影响因子：
6
通讯作者：
Ranson M
中科院分区：
文献类型：
--
作者：
Cater JH;Mañucat-Tan NB;Georgiou DK;Zhao G;Buhimschi IA;Wyatt AR;Ranson M
纤溶酶原激活物抑制剂2型（派-2）是丝氨酸蛋白酶抑制剂家族的一员，在妊娠期间和炎症反应中显著上调。尽管派-2在体内以糖基化和非糖基化形式存在，但派-2的大多数体外研究仅涉及细胞内非糖基化形式。这项研究表明，暴露于炎症相关的次氯酸盐诱导派-2的寡聚化通过一种机制，涉及二酪氨酸的形成。与纤溶酶原激活物抑制剂1型（派-1）相比，两种形式的派-2对次氯酸盐诱导的其蛋白酶抑制活性的失活更具抗性。Holdase型细胞外伴侣活性对派-2起着假定的非典型作用。我们的数据表明，与非糖基化派-2相比，糖基化派-2在体外更有效地抑制阿尔茨海默病和先兆子痫相关淀粉样β肽（Aβ）的聚集。然而，次氯酸盐诱导的非糖基化派-2的修饰通过促进非常高分子量的分子伴侣活性派-2寡聚体的形成而显著增强其保持酶活性。两种派-2形式均在体外保护SH-SY 5 Y神经母细胞瘤细胞系免受Aβ诱导的细胞毒性。在绒毛状胎盘中，派-2主要定位于合体滋养层，在先兆子痫妇女和孕龄匹配的对照组中具有广泛的人际差异。虽然细胞内派-2和Aβ染色定位于不同的胎盘细胞类型，但在先兆子痫胎盘中丰富的细胞外斑块样聚集沉积物中，一些派-2与Aβ共定位。因此，派-2可能有助于控制异常纤维蛋白溶解和错误折叠蛋白在以氧化和蛋白质稳态应激为特征的状态下的积累，例如在阿尔茨海默病和先兆子痫中。
Plasminogen activator inhibitor type-2 (PAI-2), a member of the serpin family, is dramatically upregulated during pregnancy and in response to inflammation. Although PAI-2 exists in glycosylated and non-glycosylated forms in vivo, the majority of in vitro studies of PAI-2 have exclusively involved the intracellular non-glycosylated form. This study shows that exposure to inflammation-associated hypochlorite induces the oligomerisation of PAI-2 via a mechanism involving dityrosine formation. Compared to plasminogen activator inhibitor type-1 (PAI-1), both forms of PAI-2 are more resistant to hypochlorite-induced inactivation of its protease inhibitory activity. Holdase-type extracellular chaperone activity plays a putative non-canonical role for PAI-2. Our data demonstrate that glycosylated PAI-2 more efficiently inhibits the aggregation of Alzheimer’s disease and preeclampsia-associated amyloid beta peptide (Aβ), compared to non-glycosylated PAI-2 in vitro. However, hypochlorite-induced modification of non-glycosylated PAI-2 dramatically enhances its holdase activity by promoting the formation of very high-molecular-mass chaperone-active PAI-2 oligomers. Both PAI-2 forms protect against Aβ-induced cytotoxicity in the SH-SY5Y neuroblastoma cell line in vitro. In the villous placenta, PAI-2 is localised primarily to syncytiotrophoblast with wide interpersonal variation in women with preeclampsia and in gestational-age-matched controls. Although intracellular PAI-2 and Aβ staining localised to different placental cell types, some PAI-2 co-localised with Aβ in the extracellular plaque-like aggregated deposits abundant in preeclamptic placenta. Thus, PAI-2 potentially contributes to controlling aberrant fibrinolysis and the accumulation of misfolded proteins in states characterised by oxidative and proteostasis stress, such as in Alzheimer’s disease and preeclampsia.
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