Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD 20892-4370.
Section on Biological Chemistry, NIDCR, NIH, Bethesda, MD 20892-4370.
Proc Natl Acad Sci U S A. 2021 Nov 23;118(47). doi: 10.1073/pnas.2109905118.
The SARS-CoV-2 coronavirus responsible for the global pandemic contains a novel furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation in cells. Here, we show that -glycosylation near the furin cleavage site is mediated by members of the GALNT enzyme family, resulting in decreased furin cleavage and decreased syncytia formation. Moreover, we show that -glycosylation is dependent on the novel proline at position 681 (P681). Mutations of P681 seen in the highly transmissible alpha and delta variants abrogate -glycosylation, increase furin cleavage, and increase syncytia formation. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that host -glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the role of the P681 mutations found in the highly transmissible alpha and delta variants.
导致全球大流行的 SARS-CoV-2 冠状病毒在其刺突蛋白（S）中含有一个新型的弗林蛋白酶裂解位点，这增加了病毒在细胞中的感染力和合胞体的形成。在这里，我们表明，弗林蛋白酶裂解位点附近的 -糖基化是由 GALNT 酶家族的成员介导的，导致弗林蛋白酶裂解减少和合胞体形成减少。此外，我们表明 -糖基化依赖于位置 681 处的新型脯氨酸（P681）。在高传染性的阿尔法和德尔塔变体中观察到的 P681 突变会破坏 -糖基化，增加弗林蛋白酶裂解，并增加合胞体形成。最后，我们表明能够对 S 进行糖基化的 GALNT 家族成员在人类呼吸道细胞中表达，这些细胞是 SARS-CoV-2 感染的靶标。我们的结果表明，宿主 -糖基化可能通过调节 S 的弗林蛋白酶裂解来影响病毒的感染力/嗜性，并为在高传染性的阿尔法和德尔塔变体中发现的 P681 突变的作用提供了机制上的见解。
