Unfolded protein response (UPR) and endoplasmic reticulum (ER) stress are aspects of SARS-CoV-2-host cell interaction with proposed role in the cytopathic and inflammatory pathogenesis of this viral infection. The role of the NF-kB pathway in these cellular processes remains poorly characterized. When investigated in VERO-E6 cells, SARS-CoV-2 infection was found to markedly stimulate NF-kB protein expression and activity. NF-kB activation occurs early in the infection process (6 hpi) and it is associated with increased MAPK signaling and expression of the UPR inducer IRE-1α. These signal transduction processes characterize the cellular stress response to the virus promoting a pro-inflammatory environment and caspase activation in the host cell. Inhibition of viral replication by the viral protease inhibitor Nelfinavir reverts all these molecular changes also stimulating c-Jun expression, a key component of the JNK/AP-1 pathway with important role in the IRE-1α-mediated transcriptional regulation of stress response genes with anti-inflammatory and cytoprotection function. The present study demonstrates that UPR signaling and its interaction with cellular MAPKs and the NF-kB activity are important aspects of SARS-CoV-2-host cell interaction that deserve further investigation to identify more efficient therapies for this viral infection.

中文翻译：

---

SARS-CoV-2感染细胞的内质网应激和NF-kB活化及其对抗病毒治疗的反应

未折叠蛋白反应 (UPR) 和内质网 (ER) 应激是 SARS-CoV-2 宿主细胞相互作用的方面，并在这种病毒感染的细胞病变和炎症发病机制中提出了作用。NF-kB 通路在这些细胞过程中的作用仍然很差。在 VERO-E6 细胞中进行研究时，发现 SARS-CoV-2 感染可显着刺激 NF-kB 蛋白的表达和活性。NF-kB 激活发生在感染过程的早期（6 hpi），它与增加的 MAPK 信号传导和 UPR 诱导剂 IRE-1α 的表达有关。这些信号转导过程表征了细胞对病毒的应激反应，促进了宿主细胞中的促炎环境和半胱天冬酶活化。c -Jun 表达是 JNK/AP-1 通路的关键组成部分，在 IRE-1α 介导的具有抗炎和细胞保护功能的应激反应基因的转录调节中起重要作用。本研究表明，UPR 信号及其与细胞 MAPK 和 NF-kB 活性的相互作用是 SARS-CoV-2 与宿主细胞相互作用的重要方面，值得进一步研究以确定针对这种病毒感染的更有效疗法。