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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regulation of inducible nitric oxide synthase by rapid cellular turnover and cotranslational down-regulation by dimerization inhibitors.
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Regulation of inducible nitric oxide synthase by rapid cellular turnover and cotranslational down-regulation by dimerization inhibitors.

机译：通过快速细胞更新和二聚化抑制剂的共翻译下调来调节诱导型一氧化氮合酶。

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Overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of many disorders. iNOS is notably distinguished from constitutive NOSs by its production of large amounts of NO for a prolonged period; hence, it was termed the high-output NOS. Understanding how cells regulate iNOS is a prerequisite for strategies aimed at modulating NO synthesis. iNOS is thought to be regulated primarily at the transcriptional level in response to cytokines and inflammatory mediators. In this study, we report a posttranslational regulatory mechanism for control of iNOS expression through a rapid cellular rate of turnover. Unexpectedly, iNOS cellular half-life was found to be relatively short. In primary bronchial epithelial cells, iNOS half-life was 1.6 +/- 0.3 h. A similar half-life was found for iNOS in several cell lines. This fast rate of turnover is in sharp contrast to that reported for the constitutive NOS isoforms. iNOS half-life was not affected by intracellular depletion of tetrahydrobiopterin, a critical cofactor required for iNOS activity. Further, iNOS monomers and dimers had a similar half-life. Importantly, we discovered a previously unrecognized cotranslational down-regulation mechanism by which the newly discovered pyrimidineimidazole-based allosteric dimerization inhibitors of iNOS lead to reduced iNOS expression. This study provides insights into the cellular posttranslational mechanisms of iNOS and has important implications for design of selective iNOS inhibitors and their use in therapeutic strategies.
机译：诱导型一氧化氮合酶（iNOS）过量生产一氧化氮（NO）与许多疾病的发病机制有关。 iNOS与组成型NOS的显着区别在于，它长时间产生大量的NO。因此，它被称为高输出NOS。了解细胞如何调节iNOS是旨在调节NO合成的策略的前提。据认为，iNOS主要在转录水平上对细胞因子和炎性介质做出反应。在这项研究中，我们报告了翻译后调控机制，通过快速的细胞更新率来控制iNOS的表达。出乎意料的是，发现iNOS细胞的半衰期相对较短。在原发性支气管上皮细胞中，iNOS半衰期为1.6 +/- 0.3 h。在几种细胞系中发现了iNOS相似的半衰期。这种快速的周转率与本构型NOS亚型所报道的周转率形成鲜明对比。 iNOS的半衰期不受细胞内四氢生物蝶呤的消耗的影响，四氢生物蝶呤是iNOS活性所需的关键辅助因子。此外，iNOS单体和二聚体具有相似的半衰期。重要的是，我们发现了以前无法识别的共翻译下调机制，通过该机制，新发现的基于iNOS的嘧啶咪唑的变构二聚抑制剂导致iNOS表达降低。这项研究提供了有关iNOS的细胞翻译后机制的见解，并对选择性iNOS抑制剂的设计及其在治疗策略中的应用具有重要意义。

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