Spike (S) protein cleavage is a crucial step in coronavirus infection. In this review, this process is discussed, with particular focus on the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compared with influenza virus and paramyxovirus membrane fusion proteins, the cleavage activation mechanism of coronavirus S protein is much more complex. The S protein has two cleavage sites (S1/S2 and S2′), and the cleavage motif for furin protease at the S1/S2 site that results from a unique four-amino acid insertion is one of the distinguishing features of SARS-CoV-2. The viral particle incorporates the S protein, which has already undergone S1/S2 cleavage by furin, and then undergoes further cleavage at the S2′ site, mediated by the type II transmembrane serine protease transmembrane protease serine 2 (TMPRSS2), after binding to the receptor angiotensin-converting enzyme 2 (ACE2) to facilitate membrane fusion at the plasma membrane. In addition, SARS-CoV-2 can enter the cell by endocytosis and be proteolytically activated by cathepsin L, although this is not a major mode of SARS-CoV-2 infection. SARS-CoV-2 variants with enhanced infectivity have been emerging throughout the ongoing pandemic, and there is a close relationship between enhanced infectivity and changes in S protein cleavability. All four variants of concern carry the D614G mutation, which indirectly enhances S1/S2 cleavability by furin. The P681R mutation of the delta variant directly increases S1/S2 cleavability, enhancing membrane fusion and SARS-CoV-2 virulence. Changes in S protein cleavability can significantly impact viral infectivity, tissue tropism, and virulence. Understanding these mechanisms is critical to counteracting the coronavirus pandemic.

中文翻译：

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SARS-CoV-2 刺突蛋白的蛋白水解激活

刺突 (S) 蛋白裂解是冠状病毒感染的关键步骤。在这篇综述中，我们讨论了这一过程，特别关注新型冠状病毒，即严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)。与流感病毒和副粘病毒膜融合蛋白相比，冠状病毒S蛋白的裂解激活机制要复杂得多。S 蛋白有两个切割位点（S1/S2 和 S2'），弗林蛋白酶在 S1/S2 位点的切割基序是由独特的四个氨基酸插入产生的，这是 SARS-CoV- 的显着特征之一。 2. 病毒颗粒掺入已经被弗林蛋白酶S1/S2裂解的S蛋白，然后在S2'位点进一步裂解，由II型跨膜丝氨酸蛋白酶跨膜蛋白酶丝氨酸2（TMPRSS2）介导，在与受体血管紧张素转换酶 2 (ACE2) 结合以促进质膜处的膜融合后。此外，SARS-CoV-2 可以通过内吞作用进入细胞并被组织蛋白酶 L 蛋白水解激活，尽管这不是 SARS-CoV-2 感染的主要方式。在整个持续的大流行中，具有增强传染性的 SARS-CoV-2 变体不断出现，增强的传染性与 S 蛋白可切割性的变化之间存在密切关系。所有四个关注的变体都携带 D614G 突变，这间接增强了弗林蛋白酶的 S1/S2 切割能力。delta 变体的 P681R 突变直接增加了 S1/S2 的可切割性，增强了膜融合和 SARS-CoV-2 的毒力。S 蛋白裂解能力的变化会显着影响病毒的传染性、组织嗜性和毒力。