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QTQTN motif upstream of the furin-cleavage site plays a key role in SARS-CoV-2 infection and pathogenesis.
Vu, Michelle N; Lokugamage, Kumari G; Plante, Jessica A; Scharton, Dionna; Bailey, Aaron O; Sotcheff, Stephanea; Swetnam, Daniele M; Johnson, Bryan A; Schindewolf, Craig; Alvarado, R Elias; Crocquet-Valdes, Patricia A; Debbink, Kari; Weaver, Scott C; Walker, David H; Russell, William K; Routh, Andrew L; Plante, Kenneth S; Menachery, Vineet D.
  • Vu MN; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
  • Lokugamage KG; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
  • Plante JA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
  • Scharton D; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX 77555.
  • Bailey AO; World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX 77555.
  • Sotcheff S; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
  • Swetnam DM; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX 77555.
  • Johnson BA; World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX 77555.
  • Schindewolf C; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555.
  • Alvarado RE; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555.
  • Crocquet-Valdes PA; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555.
  • Debbink K; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
  • Weaver SC; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
  • Walker DH; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
  • Russell WK; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX.
  • Routh AL; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555.
  • Plante KS; Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21211.
  • Menachery VD; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
Proc Natl Acad Sci U S A ; 119(32): e2205690119, 2022 08 09.
Article in English | MEDLINE | ID: covidwho-2311515
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Furin / Proteolysis / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Proc Natl Acad Sci U S A Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Furin / Proteolysis / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Proc Natl Acad Sci U S A Year: 2022 Document Type: Article