Tight junction protein occludin is an internalization factor for SARS-CoV-2 infection and mediates virus cell-to-cell transmission.
Tight junction protein occludin is an internalization factor for SARS-CoV-2 infection and mediates virus cell-to-cell transmission.
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DOI：
10.1073/pnas.2218623120
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发表时间：
2023-04-25
影响因子：
11.1
通讯作者：
Ma, Wenjun
中科院分区：
文献类型：
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作者：
Zhang, Jialin;Yang, Wenyu;Roy, Sawrab;Liu, Heidi;Roberts, R. Michael;Wang, Liping;Shi, Lei;Ma, Wenjun
尽管SARS-CoV-2的初始感染是通过其刺突蛋白与血管紧张素转换酶2 （ACE2）受体结合的细胞表面进入途径发生的，但随后的传播主要涉及直接的细胞间传播和合胞体的形成，其中所需的宿主因子在很大程度上仍然未知。在这里，我们证明了紧密连接蛋白闭塞蛋白（OCLN）是这些事件的关键内化因子。OCLN结合刺突蛋白并介导细胞间病毒传播。原型和变型SARS-CoV-2毒株的细胞间传播依赖于刺突蛋白与OCLN的结合，尽管随后合胞体形成的程度依赖于毒株。我们的研究结果将有助于更好地了解SARS-CoV-2的进入、传播和发病机制。严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）通过刺突介导的直接细胞间传播有效传播。然而，人们对其潜在机制知之甚少。在这里，我们证明了紧密连接蛋白闭塞蛋白（OCLN）在这个过程中是至关重要的。SARS-CoV-2感染会改变OCLN的分布和表达，并导致合胞体形成，从而导致病毒传播。OCLN敲低不能改变SARS-CoV-2的结合，但显著降低内化、合胞体形成和传播。OCLN过表达对病毒结合也没有影响，但会增强病毒内化、细胞间传播和复制。OCLN直接与SARS-CoV-2刺突相互作用，并且内体进入途径参与OCLN介导的细胞间融合，而不是参与细胞表面进入途径。所有测试的SARS-CoV-2菌株（原型、α、β、γ、δ、kappa和组粒）都依赖于OCLN进行细胞间传播，尽管菌株之间合胞体形成的程度不同。我们得出结论，SARS-CoV-2利用OCLN作为细胞间传播的内化因子。
Although initial infection by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs via a cell surface entry pathway through its spike protein binding to the angiotensin-converting enzyme 2 (ACE2) receptor, subsequent spread largely involves direct cell-to-cell transmission and syncytium formation, processes in which host factors required remain largely unknown. Here, we demonstrate that the tight junction protein occludin (OCLN) is a key internalization factor critical for these events. OCLN binds the spike protein and mediates cell-to-cell virus transmission. Cell-to-cell transmission of both prototypic and variant SARS-CoV-2 strains is reliant on spike protein binding to OCLN, even though the extent of subsequent syncytium formation is virus strain dependent. Our results will provide a better understanding of SARS-CoV-2 entry, transmission, and pathogenesis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads efficiently by spike-mediated, direct cell-to-cell transmission. However, the underlying mechanism is poorly understood. Herein, we demonstrate that the tight junction protein occludin (OCLN) is critical to this process. SARS-CoV-2 infection alters OCLN distribution and expression and causes syncytium formation that leads to viral spread. OCLN knockdown fails to alter SARS-CoV-2 binding but significantly lowers internalization, syncytium formation, and transmission. OCLN overexpression also has no effect on virus binding but enhances virus internalization, cell-to-cell transmission, and replication. OCLN directly interacts with the SARS-CoV-2 spike, and the endosomal entry pathway is involved in OCLN-mediated cell-to-cell fusion rather than in the cell surface entry pathway. All SARS-CoV-2 strains tested (prototypic, alpha, beta, gamma, delta, kappa, and omicron) are dependent on OCLN for cell-to-cell transmission, although the extent of syncytium formation differs between strains. We conclude that SARS-CoV-2 utilizes OCLN as an internalization factor for cell-to-cell transmission.
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影响因子：
64.5
作者：
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通讯作者：
Baric, Ralph S.
影响因子：
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