ArticleProceedings of the National Academy of Sciences of the United States of America2022
QTQTN motif upstream of the furin-cleavage site plays a key role in SARS-CoV-2 infection and pathogenesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 48 citations in OpenAlex.
- The conserved QTQTX motif in the SARS-CoV-2 spike protein is dispensable for cleavage and lung cell entry of the emerging variant BA.3.2.Journal of virology · 2026Article
- Loss-of-function mutation in Omicron variants reduces spike protein expression and attenuates SARS-CoV-2 infection.Nature communications · 2026Article
- SARS-CoV-2 EndoU-ribonuclease regulates RNA recombination and impacts viral fitness.Nature communications · 2025Article
- Recombination alters the receptor binding and furin cleavage site in novel bat-borne HKU5-CoV-2 coronavirus.Microbiology spectrum · 2025Article
- Host cell and viral protease targets of human SERPINs identified by in silico docking.The EMBO journal · 2025Article
- The furin cleavage site is required for pathogenesis, but not transmission, of SARS-CoV-2.Journal of virology · 2025Article
- Long-term serial passaging of SARS-CoV-2 reveals signatures of convergent evolution.Journal of virology · 2025Article
- Variant mutation G215C in SARS-CoV-2 nucleocapsid enhances viral infection via altered genomic encapsidation.PLoS biology · 2025Article
- The furin cleavage site is required for pathogenesis, but not transmission of SARS-CoV-2.bioRxiv : the preprint server for biology · 2025Article
- Replication differences of SARS-CoV-2 lineages may arise from unique RNA replication characteristics and nucleocapsid protein expression.Frontiers in cellular and infection microbiology · 2025Article
- Insights into the Replication Kinetics Profiles of Malaysian SARS-CoV-2 Variant Alpha, Beta, Delta, and Omicron in Vero E6 Cell Line.International journal of molecular sciences · 2024Article
- SARS-CoV-2 Omicron subvariants progressively adapt to human cells with altered host cell entry.mSphere · 2024Article
- Article
- Vero cell-adapted SARS-CoV-2 strain shows increased viral growth through furin-mediated efficient spike cleavage.Microbiology spectrum · 2024Article
- The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions.EMBO reports · 2024Article
- Comparison of SARS-CoV-2 variants of concern in primary human nasal cultures demonstrates Delta as most cytopathic and Omicron as fastest replicating.bioRxiv : the preprint server for biology · 2023Article
- Reverse genetics systems for SARS-CoV-2: Development and applications.Virologica Sinica · 2023Review
- Coronavirus 2'-O-methyltransferase: A promising therapeutic target.Virus research · 2023Review
- Host range, transmissibility and antigenicity of a pangolin coronavirus.Nature microbiology · 2023Article
- SARS-CoV-2 hijacks fragile X mental retardation proteins for efficient infection.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
Abstract
The furin cleavage site (FCS), an unusual feature in the SARS-CoV-2 spike protein, has been spotlighted as a factor key to facilitating infection and pathogenesis by increasing spike processing. Similarly, the QTQTN motif directly upstream of the FCS is also an unusual feature for group 2B coronaviruses (CoVs). The QTQTN deletion has consistently been observed in in vitro cultured virus stocks and some clinical isolates. To determine whether the QTQTN motif is critical to SARS-CoV-2 replication and pathogenesis, we generated a mutant deleting the QTQTN motif (ΔQTQTN). Here, we report that the QTQTN deletion attenuates viral replication in respiratory cells in vitro and attenuates disease in vivo. The deletion results in a shortened, more rigid peptide loop that contains the FCS and is less accessible to host proteases, such as TMPRSS2. Thus, the deletion reduced the efficiency of spike processing and attenuates SARS-CoV-2 infection. Importantly, the QTQTN motif also contains residues that are glycosylated, and disruption of its glycosylation also attenuates virus replication in a TMPRSS2-dependent manner. Together, our results reveal that three aspects of the S1/S2 cleavage site-the FCS, loop length, and glycosylation-are required for efficient SARS-CoV-2 replication and pathogenesis.
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