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首页> 外文期刊>Cellular Signalling >Protein phosphatase 2A carboxymethylation and regulatory B subunits differentially regulate mast cell degranulation
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Protein phosphatase 2A carboxymethylation and regulatory B subunits differentially regulate mast cell degranulation

机译：蛋白磷酸酶2A羧甲基化和调节性B亚基差异调节肥大细胞脱粒

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Asthma is characterised by antigen-mediated mast cell degranulation resulting in secretion of inflammatory mediators. Protein phosphatase 2A (PP2A) is a serine/threonine protein phosphatase composed of a catalytic (PP2A-C) subunit together with a core scaffold (PP2A-A) subunit and a variable, regulatory (PP2A-B) subunit. Previous studies utilising pharmacological inhibition of protein phosphatases have suggested a positive regulatory role for PP2A in mast cell degranulation. In support of this we find that a high okadaic acid concentration (1. μM) inhibits mast cell degranulation. Strikingly, we now show that a low concentration of okadaic acid (0.1 μM) has the opposite effect, resulting in enhanced degranulation. Selective downregulation of the PP2A-Cα subunit by short hairpin RNA also enhanced degranulation of RBL-2H3 mast cells, suggesting that the primary role of PP2A is to negatively regulate degranulation. PP2A-B subunits are responsible for substrate specificity, and carboxymethylation of the PP2A-C subunit alters B subunit binding. We show here that carboxymethylation of PP2A-C is dynamically altered during degranulation and inhibition of methylation decreases degranulation. Moreover downregulation of the PP2A-Bα subunit resulted in decreased MK2 phosphorylation and degranulation, whilst downregulation of the PP2A-B'δ subunit enhanced p38 MAPK phosphorylation and degranulation. Taken together these data show that PP2A is both a positive and negative regulator of mast cell degranulation, and this differential role is regulated by carboxymethylation and specific PP2A-B subunit binding.
机译：哮喘的特征是抗原介导的肥大细胞脱粒，导致炎症介质的分泌。蛋白磷酸酶2A（PP2A）是一种丝氨酸/苏氨酸蛋白磷酸酶，由催化（PP2A-C）亚基，核心支架（PP2A-A）亚基和可变的调节性（PP2A-B）亚基组成。先前利用蛋白质磷酸酶的药理学抑制作用的研究表明，PP2A在肥大细胞脱粒中具有积极的调节作用。为了证明这一点，我们发现高冈田酸浓度（1.μM）抑制肥大细胞脱粒。令人惊讶的是，我们现在显示低浓度的冈田酸（0.1μM）具有相反的作用，导致脱粒作用增强。短发夹RNA对PP2A-Cα亚基的选择性下调也增强了RBL-2H3肥大细胞的脱颗粒，这表明PP2A的主要作用是负调节脱颗粒。 PP2A-B亚基负责底物特异性，PP2A-C亚基的羧甲基化可改变B亚基的结合。我们在这里显示，PP2A-C的羧甲基化在脱粒过程中动态变化，抑制甲基化会降低脱粒作用。此外，PP2A-Bα亚基的下调导致MK2磷酸化和脱粒减少，而PP2A-B'δ亚基的下调增强了p38 MAPK磷酸化和脱粒。这些数据加在一起表明，PP2A既是肥大细胞脱粒的正调节剂，也是肥大细胞脱颗粒的负调节剂，这种差异作用受羧甲基化和特定PP2A-B亚基结合的调节。

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