Emerging new variants of SARS-CoV-2 and inevitable acquired drug resistance call for the continued search of new pharmacological targets to fight the potentially fatal infection. Here, we describe the mechanisms by which the E protein of SARS-CoV-2 hijacks the human transcriptional regulator BRD4. We found that SARS-CoV-2 E is acetylated in vivo and co-immunoprecipitates with BRD4 in human cells. Bromodomains (BDs) of BRD4 bind to the C-terminus of the E protein, acetylated by human acetyltransferase p300, whereas the ET domain of BRD4 recognizes the unmodified motif of the E protein. Inhibitors of BRD4 BDs, JQ1 or OTX015, decrease SARS-CoV-2 infectivity in lung bronchial epithelial cells, indicating that the acetyllysine binding function of BDs is necessary for the virus fitness and that BRD4 represents a potential anti-COVID-19 target. Our findings provide insight into molecular mechanisms that contribute to SARS-CoV-2 pathogenesis and shed light on a new strategy to block SARS-CoV-2 infection.

SARS-CoV-2 的新变种的出现和不可避免的获得性耐药性要求继续寻找新的药理学靶点来对抗潜在的致命感染。在这里，我们描述了 SARS-CoV-2 的 E 蛋白劫持人类转录调节因子 BRD4 的机制。我们发现 SARS-CoV-2 E在体内被乙酰化，并在人体细胞中与 BRD4 发生共免疫沉淀。 BRD4 的溴结构域 (BD) 与 E 蛋白的 C 末端结合，并被人乙酰转移酶 p300 乙酰化，而 BRD4 的 ET 结构域则识别 E 蛋白的未修饰基序。 BRD4 BD 抑制剂 JQ1 或 OTX015 可降低肺支气管上皮细胞中的 SARS-CoV-2 感染性，表明 BD 的乙酰赖氨酸结合功能对于病毒适应性是必需的，并且 BRD4 代表了潜在的抗 COVID-19 靶点。我们的研究结果提供了对 SARS-CoV-2 发病机制的分子机制的深入了解，并揭示了阻止 SARS-CoV-2 感染的新策略。