QTQTN motif upstream of the furin-cleavage site plays a key role in SARS-CoV-2 infection and pathogenesis

Michelle N. Vu, Kumari G. Lokugamage, Jessica Plante, Dionna Scharton, Aaron O. Bailey, Stephanea Sotcheff, Daniele Swetnam, Bryan A. Johnson, Craig Schindewolf, R. Elias Alvarado, Patricia A. Crocquet-Valdes, Kari Debbink, Scott C. Weaver, David H. Walker, William K. Russell, Andrew Routh, Kenneth S. Plante, Vineet D. Menachery

Research output: Contribution to journalArticlepeer-review


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 SARSCoV- 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.

Original languageEnglish (US)
Article numbere2205690119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number32
StatePublished - Aug 9 2022


  • SARS-CoV-2
  • furin cleavage site
  • glycosylation
  • spike

ASJC Scopus subject areas

  • General


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