RhTyrRS (Y341A), a novel human tyrosyl-tRNA synthetase mutant, stimulates thrombopoiesis through activation of the VEGF-R II/NF-κB pathway
RhTyrRS (Y341A), a novel human tyrosyl-tRNA synthetase mutant, stimulates thrombopoiesis through activation of the VEGF-R II/NF-κB pathway
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RhTyrRS (Y341A) 是一种新型人酪氨酰-tRNA 合成酶突变体，通过激活 VEGF-R II/NF-κB 途径刺激血小板生成
DOI：
10.1016/j.bcp.2019.113634
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发表时间：
2019
影响因子：
5.8
通讯作者：
Jianxin Gu
中科院分区：
文献类型：
--
作者：
Yun Shi;Jinchao Yu;Yanling Zhang;Bing Zhao;Yaran Li;Yuhao Ye;Qiang Yu;Min Yu;Wei Mo;Jianxin Gu
背景与目的肿瘤化疗和放疗可诱导造血细胞损伤，导致血小板减少。传统的血小板输注策略或药物治疗用于治疗血小板减少症。然而，这些疗法可能导致一些副作用，包括对传染病的易感性增加和抗tpo抗体的形成。因此，应该探索一种更安全的策略来克服和弥补传统策略的不足。实验方法通过分析mRNA表达、启动子活性、蛋白表达，确定rhTyrRS（Y341A）对HUVECs表面VCAM-1表达的影响。通过检测VEGF-R II/NF-κB通路的激活情况，探讨rhTyrRS（Y341A）影响HUVECs表面VCAM-1表达的分子机制。我们的研究结果证明，rhTyrRS （Y341A）激活NF-κB，以VEGF-R II/NF-κB途径依赖的方式上调VCAM-1，导致巨核细胞粘附在pvec上，诱导血小板产生。结论在正常情况下，一种新的人酪氨酸- trna合成酶突变rtyrrs （Y341A）可增加血小板计数。此外，我们证实了NF-κ b介导的机制参与了rhTyrRS （Y341A）诱导的血栓形成，这涉及到它与VEGF-R II的相互作用。
Bacground and purposeTumor chemotherapy and radiotherapy induces hematopoietic cell damage, resulting in thrombocytopenia. Conventional platelet transfusion strategies or drug therapies are used to treat thrombocytopenia. However, these therapies may result in a several side effects, including heightened susceptibility to infectious diseases and the formation of anti-TPO-antibodies. Therefore, a more secure strategy should be explored to overcome and compensate for the shortcomings of conventional strategies.Experimental approachEffects of rhTyrRS(Y341A) on the expression of VCAM-1 on the surface of HUVECs were determined by analysing mRNA expression, promoter activity, protein expression. The molecular mechanisms of the effects of rhTyrRS(Y341A) on the expression of VCAM-1 on the surface of HUVECs were investigated by determining the activation of VEGF-R II/NF-κB pathway.Key resultsOur results provide evidence that rhTyrRS (Y341A) activates NF-κB to upregulate VCAM-1 in a VEGF-R II/NF-κB pathway-dependent, resulting in megakaryocyte adhering to PVECs to induce platelet production.ConclusionsThis study suggested that rhTyrRS (Y341A), a novel human tyrosyl-tRNA synthetase mutation, increased the platelet count under normal conditions. Further more, we confirmed that an NF-κB-mediated mechanism is involved in rhTyrRS (Y341A)-induced thrombopoiesis, which involves its interaction with VEGF-R II.