Inhibition of LDHA to induce eEF2 release enhances thrombocytopoiesis
Inhibition of LDHA to induce eEF2 release enhances thrombocytopoiesis
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抑制 LDHA 诱导 EEF2 释放增强血小板生成
DOI：
10.1182/blood.2022015620
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发表时间：
2022-05-12
期刊：
影响因子：
20.3
通讯作者：
Fan, Xuemei
中科院分区：
文献类型：
--
作者：
Chen, Qidi;Xin, Min;Fan, Xuemei
翻译对于巨核细胞 (MK) 成熟和血小板生成至关重要。然而，在此过程中翻译途径是如何调节的仍然未知。在这项研究中，我们发现 MK/血小板特异性乳酸脱氢酶 A (LdhA) 敲除小鼠表现出血小板数量增加，并且 MK 成熟和前血小板形成显着加速。有趣的是，LDHA 在 MK 成熟和血小板形成中的作用并不依赖于乳酸含量，而乳酸含量是 LDHA 的主要产物。机制研究表明，LDHA 与细胞质中的真核延伸因子 2 (eEF2) 相互作用，控制 eEF2 在核糖体翻译中的参与。此外，LDHA 和 eEF2 的相互作用依赖于 LDHA 的辅酶烟酰胺腺嘌呤二核苷酸 (NADH)。 LDHA 的 NADH 竞争性抑制剂可以从 LDHA 池中释放 eEF2，上调翻译并增强体外 MK 成熟。在LDHA抑制剂中，司替戊醇在生理状态下和免疫性血小板减少模型中显着促进体内血小板的产生。此外，司替戊醇可以促进人脐带血单核细胞衍生的 MK 产生血小板，并且与 romiplostim 也有叠加作用。简而言之，这项研究显示了 LDHA 在翻译中的一种新颖的非经典功能，可以作为血小板减少症治疗的潜在靶点。
Translation is essential for megakaryocyte (MK) maturation and platelet production. However, how the translational pathways are regulated in this process remains unknown. In this study, we found that MK/platelet-specific lactate dehydrogenase A (LdhA) knockout mice exhibited an increased number of platelets with remarkably accelerated MK maturation and proplatelet formation. Interestingly, the role of LDHA in MK maturation and platelet formation did not depend on lactate content, which was the major product of LDHA. Mechanism studies revealed that LDHA interacted with eukaryotic elongation factor 2 (eEF2) in the cytoplasm, controlling the participation of eEF2 in translation at the ribosome. Furthermore, the interaction of LDHA and eEF2 was dependent on nicotinamide adenine dinucleotide (NADH), a coenzyme of LDHA. NADH-competitive inhibitors of LDHA could release eEF2 from the LDHA pool, upregulate translation, and enhance MK maturation in vitro. Among LDHA inhibitors, stiripentol significantly promoted the production of platelets in vivo under a physiological state and in the immune thrombocytopenia model. Moreover, stiripentol could promote platelet production from human cord blood mononuclear cell-derived MKs and also have a superposed effect with romiplostim. In short, this study shows a novel nonclassical function of LDHA in translation that may serve as a potential target for thrombocytopenia therapy.