The IFN-induced protein IFI27 binds MDA5 and counteracts its activation after SARS-CoV-2 infection

Front Cell Infect Microbiol. 2024 Oct 4:14:1470924. doi: 10.3389/fcimb.2024.1470924. eCollection 2024.

Abstract

Innate immune responses are induced after viral infections, being these responses essential to establish an antiviral response in the host. The RIG-I-like receptors (RLRs), RIG-I and MDA5 are pivotal for virus detection by recognizing viral RNAs in the cytoplasm of infected cells, initiating these responses. However, since excessive responses can have a negative effect on the host, regulatory feedback mechanisms are needed. In this work, we describe that IFN alpha-inducible protein 27 (IFI27) co-immunoprecipitates with melanoma differentiation-associated protein 5 (MDA5), being this interaction likely mediated by RNAs. In addition, by using IFI27 overexpression, knock-out, and knock-down cells, we show that IFI27 inhibits MDA5 oligomerization and activation, counteracting the innate immune responses induced after SARS-CoV-2 infections or after polyinosinic-polycytidylic acid (poly(I:C)) transfection. Furthermore, our data indicate that IFI27 competes with MDA5 for poly(I:C) binding, providing a likely explanation for the effect of IFI27 in inhibiting MDA5 activation. This new function of IFI27 could be used to design target-driven compounds to treat diseases associated with an exacerbated induction of innate immune responses, such as those induced by SARS-CoV-2.

Keywords: IFI27; MDA5; RIG-I-like receptors; SARS-CoV-2; inflammation; innate immune responses; innate immunity; interferon.

MeSH terms

  • COVID-19 / immunology
  • COVID-19 / metabolism
  • COVID-19 / virology
  • HEK293 Cells
  • Humans
  • Immunity, Innate*
  • Interferon-Induced Helicase, IFIH1* / genetics
  • Interferon-Induced Helicase, IFIH1* / metabolism
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Poly I-C / pharmacology
  • Protein Binding
  • RNA, Viral / metabolism
  • SARS-CoV-2* / immunology

Substances

  • Interferon-Induced Helicase, IFIH1
  • IFIH1 protein, human
  • IFI27 protein, human
  • Membrane Proteins
  • Poly I-C
  • RNA, Viral

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 grant PID-2021-123810OB-I00, funded by MCIN/ AEI /10.13039/501100011033/ and by FEDER; and by grant CNS2022-135276, funded by MCIN/AEI /10.13039/501100011033 and the European Union NextGenerationEU/PRTR, to MD. The project that gave rise to these results received the support of a fellowship from “la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/DR22/11950020 (to DL-G).