Oxysterole-binding protein targeted by SARS-CoV-2 viral proteins regulates coronavirus replication

Front Cell Infect Microbiol. 2024 Jul 25:14:1383917. doi: 10.3389/fcimb.2024.1383917. eCollection 2024.

Abstract

Introduction: Oxysterol-binding protein (OSBP) is known for its crucial role in lipid transport, facilitating cholesterol exchange between the Golgi apparatus and endoplasmic reticulum membranes. Despite its established function in cellular processes, its involvement in coronavirus replication remains unclear.

Methods: In this study, we investigated the role of OSBP in coronavirus replication and explored the potential of a novel OSBP-binding compound, ZJ-1, as an antiviral agent against coronaviruses, including SARS-CoV-2. We utilized a combination of biochemical and cellular assays to elucidate the interactions between OSBP and SARS-CoV-2 non-structural proteins (Nsps) and other viral proteins.

Results: Our findings demonstrate that OSBP positively regulates coronavirus replication. Moreover, treatment with ZJ-1 resulted in reduced OSBP levels and exhibited potent antiviral effects against multiple coronaviruses. Through our investigation, we identified specific interactions between OSBP and SARS-CoV-2 Nsps, particularly Nsp3, Nsp4, and Nsp6, which are involved in double-membrane vesicle formation-a crucial step in viral replication. Additionally, we observed that Nsp3 a.a.1-1363, Nsp4, and Nsp6 target vesicle-associated membrane protein (VAMP)-associated protein B (VAP-B), which anchors OSBP to the ER membrane. Interestingly, the interaction between OSBP and VAP-B is disrupted by Nsp3 a.a.1-1363 and partially impaired by Nsp6. Furthermore, we identified SARS-CoV-2 orf7a, orf7b, and orf3a as additional OSBP targets, with OSBP contributing to their stabilization.

Conclusion: Our study highlights the significance of OSBP in coronavirus replication and identifies it as a promising target for the development of antiviral therapies against SARS-CoV-2 and other coronaviruses. These findings underscore the potential of OSBP-targeted interventions in combating coronavirus infections.

Keywords: Nsp3; Nsp4; Nsp6; OSBP; SARS-CoV-2; VAP-B; coronavirus.

MeSH terms

  • Animals
  • Antiviral Agents* / pharmacology
  • COVID-19 / metabolism
  • COVID-19 / virology
  • Chlorocebus aethiops
  • Coronavirus Papain-Like Proteases / metabolism
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / virology
  • HEK293 Cells
  • Humans
  • Protein Binding
  • Receptors, Steroid* / metabolism
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / physiology
  • Vero Cells
  • Viral Nonstructural Proteins* / metabolism
  • Viral Proteins / metabolism
  • Viroporin Proteins / metabolism
  • Virus Replication* / drug effects

Substances

  • oxysterol binding protein
  • Antiviral Agents
  • Receptors, Steroid
  • Viral Nonstructural Proteins
  • Viral Proteins
  • Viroporin Proteins
  • Coronavirus Papain-Like Proteases
  • ORF7a protein, SARS-CoV-2

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants of the “Bundesministerium fuer Bildung und Forschung” of the German Government (RAPID 01Kl1723C/01KI2006C) to AB (Ludwig-Maximilians-University Munich) and the German Center for Infection Research (DZIF, partner site Munich, project TTU EI 01.806 to AB).