The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection.
The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection.
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DOI：
10.1016/j.jbc.2021.100759
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Lee AS
中科院分区：
文献类型：
--
作者：
Carlos AJ;Ha DP;Yeh DW;Van Krieken R;Tseng CC;Zhang P;Gill P;Machida K;Lee AS
严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）是COVID-19全球大流行的病原体，利用宿主受体血管紧张素转换酶2（ACE 2）进行病毒进入。然而，其他宿主因素也可能在SARS-CoV-2感染中发挥重要作用，为抗病毒治疗提供了新的方向。GRP 78是一种应激诱导的分子伴侣，对许多病毒的进入和感染性很重要。最近的分子对接分析揭示了GRP 78和SARS-CoV-2刺突蛋白（SARS-2-S）的受体结合结构域（RBD）之间的假定相互作用。在这里，我们报告说，GRP 78可以形成一个复杂的SARS-2-S和ACE 2的表面上，并在核周区典型的内质网在VeroE 6-ACE 2细胞和GRP 78的底物结合域是这种相互作用的关键。体外结合研究进一步证实GRP 78可以直接与SARS-2-S和ACE 2的RBD结合。为了研究GRP 78在该复合物中的作用，我们敲低了VeroE 6-ACE 2细胞中的GRP 78。GRP 78的缺失显著降低了细胞表面ACE 2的表达，并导致未折叠蛋白反应的标记物的激活。用人源化单克隆抗体（hMAb 159）治疗肺上皮细胞，其在临床前模型中的安全临床特征被选择为耗尽细胞表面GRP 78和减少细胞表面ACE 2表达，以及SARS-2-S驱动的病毒进入和SARS-CoV-2体外感染。我们的数据表明，GRP 78是SARS-CoV-2进入和感染的重要宿主辅助因子，并且是对抗这种新型病原体和其他在联合治疗中利用GRP 78的病毒的潜在靶点。
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 global pandemic, utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) for viral entry. However, other host factors might also play important roles in SARS-CoV-2 infection, providing new directions for antiviral treatments. GRP78 is a stress-inducible chaperone important for entry and infectivity for many viruses. Recent molecular docking analyses revealed putative interaction between GRP78 and the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (SARS-2-S). Here we report that GRP78 can form a complex with SARS-2-S and ACE2 on the surface and at the perinuclear region typical of the endoplasmic reticulum in VeroE6-ACE2 cells and that the substrate-binding domain of GRP78 is critical for this interaction. In vitro binding studies further confirmed that GRP78 can directly bind to the RBD of SARS-2-S and ACE2. To investigate the role of GRP78 in this complex, we knocked down GRP78 in VeroE6-ACE2 cells. Loss of GRP78 markedly reduced cell surface ACE2 expression and led to activation of markers of the unfolded protein response. Treatment of lung epithelial cells with a humanized monoclonal antibody (hMAb159) selected for its safe clinical profile in preclinical models depleted cell surface GRP78 and reduced cell surface ACE2 expression, as well as SARS-2-S-driven viral entry and SARS-CoV-2 infection in vitro. Our data suggest that GRP78 is an important host auxiliary factor for SARS-CoV-2 entry and infection and a potential target to combat this novel pathogen and other viruses that utilize GRP78 in combination therapy.
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作者：
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DOI：
10.1074/jbc.ra118.001897
发表时间：
2018-07-27
期刊：
The Journal of biological chemistry
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