SARS-CoV-2 ORF3a positively regulates NF-κB activity by enhancing IKKβ-NEMO interaction

Virus Res. 2023 Apr 15:328:199086. doi: 10.1016/j.virusres.2023.199086. Epub 2023 Mar 13.

Abstract

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by SARS-CoV-2 infection. Patients with severe COVID-19 exhibit robust induction of proinflammatory cytokines, which are closely associated with the development of acute respiratory distress syndrome. However, the underlying mechanisms of the NF-κB activation mediated by SARS-CoV-2 infection remain poorly understood. Here, we screened SARS-CoV-2 genes and found that ORF3a induces proinflammatory cytokines by activating the NF-κB pathway. Moreover, we found that ORF3a interacts with IKKβ and NEMO and enhances the interaction of IKKβ-NEMO, thereby positively regulating NF-κB activity. Together, these results suggest ORF3a may play pivotal roles in the pathogenesis of SARS-CoV-2 and provide novel insights into the interaction between host immune responses and SARS-CoV-2 infection.

Keywords: IKKβ; Inflammation; NEMO; NF-κB; ORF3a; SARS-CoV-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19* / metabolism
  • Cytokines
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • NF-kappa B* / metabolism
  • Protein Serine-Threonine Kinases
  • SARS-CoV-2* / metabolism
  • Viroporin Proteins* / metabolism

Substances

  • Cytokines
  • I-kappa B Kinase
  • IKBKG protein, human
  • NF-kappa B
  • ORF3a protein, SARS-CoV-2
  • Protein Serine-Threonine Kinases
  • Viroporin Proteins