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IL4I1 binds to TMPRSS13 and competes with SARS-CoV-2 spike.

Jérôme Gatineau1, Charlotte Nidercorne2, Aurélie Dupont1

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Frontiers in Immunology
|September 22, 2022
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Summary

Interleukin-4-induced gene 1 (IL4I1) binds TMPRSS13, a protein on immune cells. This interaction may explain IL4I1's role in cancer immunosuppression and SARS-CoV-2 entry.

Keywords:
IL4I1SARS-CoV-2cancer therapyimmunosuppressive enzymesmoonlighting proteinspike

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Area of Science:

  • Immunology
  • Virology
  • Biochemistry

Background:

  • Interleukin-4-induced gene 1 (IL4I1) is a secreted enzyme that negatively regulates adaptive immunity.
  • IL4I1 expression in human cancers is linked to poor prognosis and immunotherapy resistance.
  • The precise mechanism of IL4I1's immunosuppressive function is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism of IL4I1's immunosuppressive activity.
  • To identify cellular receptors or binding partners of IL4I1.
  • To explore potential therapeutic implications for cancer and viral infections.

Main Methods:

  • Protein-protein interaction studies to identify IL4I1 binding partners.
  • Expression analysis of TMPRSS13 in human immune cells.
  • Functional assays using SARS-CoV-2 spike pseudotyped viruses to assess TMPRSS13 activity.
  • Comparative sequence analysis to identify regions of homology between IL4I1 and SARS-CoV-2 spike protein.

Main Results:

  • Transmembrane serine protease 13 (TMPRSS13) was identified as an IL4I1-binding protein expressed on human lymphocytes, monocytes, and macrophages.
  • TMPRSS13 exhibits protease activity capable of cleaving the SARS-CoV-2 spike protein, facilitating viral entry.
  • Regions of homology were found between IL4I1 and the SARS-CoV-2 spike protein, suggesting competitive binding to TMPRSS13.
  • IL4I1 and SARS-CoV-2 spike protein compete for binding to TMPRSS13.

Conclusions:

  • TMPRSS13 acts as a bridge between IL4I1 and immune cells, mediating IL4I1's immunosuppressive effects in cancer.
  • The interaction between IL4I1, TMPRSS13, and the SARS-CoV-2 spike protein offers potential therapeutic targets.
  • Understanding this interaction could lead to strategies to enhance cancer immunotherapy and inhibit SARS-CoV-2 infection.