COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads to cytokine storm
COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads to cytokine storm
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DOI：
10.1038/s41392-020-00292-7
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发表时间：
2020-09-03
影响因子：
39.3
通讯作者：
Seo, Young-Kyo
中科院分区：
文献类型：
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作者：
Lee, Wonhwa;Ahn, June Hong;Seo, Young-Kyo
固醇调节元件结合蛋白-2（SREBP-2）被细胞因子或病原体（如病毒或细菌）激活，但其与COVID-19患者胆固醇水平降低的相关性尚不清楚。在这里，我们评估了COVID-19患者外周血单核细胞中SREBP-2的活化，并验证了SREBP-2在COVID-19中的功能。有趣的是，我们报告了在COVID-19患者血液中首次观察到SREBP-2 C-末端片段，并提出SREBP-2 C-末端片段作为确定严重程度的指标。我们证实SREBP-2诱导的胆固醇生物合成受到Sestrin-1和PCSK 9表达的抑制，而SREBP-2诱导的炎症反应在COVID-19 ICU患者中上调。使用感染性疾病小鼠模型，SREBP-2和NF-κ B的抑制剂抑制由病毒感染引起的细胞因子风暴并预防肺损伤。这些结果共同表明，SREBP-2可以作为严重程度诊断的指标和预防严重COVID-19患者细胞因子风暴和肺损伤的治疗靶点。
Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-kappa B suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.