SARS-CoV-2 Spike Protein Mutation at Cysteine-488 Impairs Its Golgi Localization and Intracellular S1/S2 Processing

Yuichiro Yamamoto, Tetsuya Inoue, Miyu Inoue, Mana Murae, Masayoshi Fukasawa, Mika K. Kaneko, Yukinari Kato, Kohji Noguchi

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to the cellular receptor—angiotensin-converting enzyme-2 (ACE2) as the first step in viral cell entry. SARS-CoV-2 spike protein expression in the ACE2-expressing cell surface induces cell–cell membrane fusion, thus forming syncytia. To exert its fusogenic activity, the spike protein is typically processed at a specific site (the S1/S2 site) by cellular proteases such as furin. The C488 residue, located at the spike–ACE2 interacting surface, is critical for the fusogenic and infectious roles of the SARS-CoV-2 spike protein. We have demonstrated that the C488 residue of the spike protein is involved in subcellular targeting and S1/S2 processing. C488 mutant spike localization to the Golgi apparatus and cell surface were impaired. Consequently, the S1/S2 processing of the spike protein, probed by anti-Ser-686-cleaved spike antibody, markedly decreased in C488 mutant spike proteins. Moreover, brefeldin-A-mediated endoplasmic-reticulum-to-Golgi traffic suppression also suppressed spike protein S1/S2 processing. As brefeldin A treatment and C488 mutation inhibited S1/S2 processing and syncytia formation, the C488 residue of spike protein is required for functional spike protein processing.

Original languageEnglish
Article number15834
JournalInternational Journal of Molecular Sciences
Volume23
Issue number24
DOIs
Publication statusPublished - 2022 Dec

Keywords

  • brefeldin A
  • cysteine
  • proteolysis
  • SARS-CoV-2
  • spike

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