登革病毒蛋白酶的差异定位影响细胞稳态并引发血小板减少症。
Differential localization of dengue virus protease affects cell homeostasis and triggers to thrombocytopenia.
作者信息
Gandhi Lekha, Maisnam Deepti, Rathore Deepika, Chauhan Preeti, Bonagiri Anvesh, Venkataramana Musturi
机构信息
Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India.
出版信息
iScience. 2023 Jun 5;26(7):107024. doi: 10.1016/j.isci.2023.107024. eCollection 2023 Jul 21.
Thrombocytopenia is one of the symptoms of many virus infections which is the "hallmark" in the case of dengue virus. In this study, we show the differential localization of existing two forms of dengue virus protease, i.e., NS2BNS3 to the nucleus and NS3 to the nucleus and mitochondria. We also report a nuclear transcription factor, erythroid differentiation regulatory factor 1 (EDRF1), as the substrate for this protease. EDRF1 regulates the expression and activity of GATA1, which in turn controls spectrin synthesis. Both GATA1 and spectrins are required for platelet formation. On the other hand, we found that the mitochondrial activities will be damaged by NS3 localization which cleaves GrpEL1, a co-chaperone of mitochondrial Hsp70. Levels of both EDRF1 and GrpEL1 were found to deteriorate in dengue virus-infected clinical samples. Hence, we conclude that NS2BNS3-mediated EDRF1 cleavage and the NS3-led mitochondrial dysfunction account for thrombocytopenia.
血小板减少是许多病毒感染的症状之一，在登革病毒感染的情况下，它是“标志性”症状。在本研究中，我们展示了登革病毒蛋白酶的两种现有形式，即NS2B-NS3定位于细胞核，NS3定位于细胞核和线粒体的差异定位。我们还报告了一种核转录因子，即红细胞分化调节因子1（EDRF1），作为这种蛋白酶的底物。EDRF1调节GATA1的表达和活性，而GATA1又控制血影蛋白的合成。血小板形成需要GATA1和血影蛋白。另一方面，我们发现NS3定位于线粒体，可切割线粒体Hsp70的共伴侣蛋白GrpEL1，从而损害线粒体活性。在登革病毒感染的临床样本中，发现EDRF1和GrpEL1的水平均下降。因此，我们得出结论，NS2B-NS3介导的EDRF1切割和NS3导致的线粒体功能障碍是血小板减少的原因。
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