4.6 Article

Neutrophil Elastase and Proteinase 3 Cleavage Sites Are Adjacent to the Polybasic Sequence within the Proteolytic Sensitive Activation Loop of the SARS-CoV-2 Spike Protein

Journal

ACS OMEGA
Volume 6, Issue 10, Pages 7181-7185

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsomega.1c00363

Keywords

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Funding

  1. Nazarbayev University Faculty-Development Competitive Research Grants Program [280720FD1907]

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Serine proteases released by activated neutrophils play important roles in immune responses and can be hijacked by viruses to evade immune detection. NE and PR3, but not CatG, hydrolyze the scissile peptide bond adjacent to the polybasic amino acid sequence of S1/S2 interface in SARS-CoV-2, suggesting their involvement in priming the virus during an immune response.
Serine proteases neutrophil elastase (NE), protease 3 (PR3), cathepsin G (CatG), and neutrophil serine protease 4 (NSP4) are released by activated neutrophils swarming around the place of pathogen invasion to provoke an immune response. However, uncontrolled proteolytic activity of proteases results in various human diseases, including cardiovascular diseases, thrombosis, and autoimmunity. In addition, proteases can be hijacked by several viruses to prime virus-derived surface proteins and evade immune detection by entering into the host cell. Indeed, porcine elastase increases the suitability of host cells to be infected by SARS-CoV-1. We compared the cleavage sites of human NE, PR3, and CatG as well as porcine-derived trypsin within the amino acid sequence of the proteolytic sensitive activation loop at the interface of S1/S2 of the spike protein (S protein) of SARS-CoV-1 as well as SARS-CoV-2. As a result, NE and PR3, but not CatG, hydrolyze the scissile peptide bond adjacent to the polybasic amino acid sequence of the S1/S2 interface of SARS-CoV-2, which is distinctive from SARS-CoV-1. These findings suggest that neutrophil-derived NE and PR3 participate in priming of the S1/S2 interface during an immune response.

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