Transglutaminase 2 Regulates Innate Immunity by Modulating the STING/TBK1/IRF3 Axis

J Immunol. 2021 May 15;206(10):2420-2429. doi: 10.4049/jimmunol.2001122. Epub 2021 May 3.

Abstract

We have recently shown that type 2 transglutaminase (TG2) plays a key role in the host's inflammatory response during bacterial infections. In this study, we investigated whether the enzyme is involved in the regulation of the STING pathway, which is the main signaling activated in the presence of both self- and pathogen DNA in the cytoplasm, leading to type I IFN (IFN I) production. In this study, we demonstrated that TG2 negatively regulates STING signaling by impairing IRF3 phosphorylation in bone marrow-derived macrophages, isolated from wild-type and TG2 knockout mice. In the absence of TG2, we found an increase in the IFN-β production and in the downstream JAK/STAT pathway activation. Interestingly, proteomic analysis revealed that TG2 interacts with TBK1, affecting its interactome composition. Indeed, TG2 ablation facilitates the TBK1-IRF3 interaction, thus indicating that the enzyme plays a negative regulatory effect on IRF3 recruitment in the STING/TBK1 complex. In keeping with these findings, we observed an increase in the IFNβ production in bronchoalveolar lavage fluids from COVID-19-positive dead patients paralleled by a dramatic decrease of the TG2 expression in the lung pneumocytes. Taken together, these results suggest that TG2 plays a negative regulation on the IFN-β production associated with the innate immunity response to the cytosolic presence of both self- and pathogen DNA.

MeSH terms

  • Animals
  • COVID-19 / genetics
  • COVID-19 / immunology*
  • COVID-19 / pathology
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / immunology*
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / immunology*
  • Interferon-beta / genetics
  • Interferon-beta / immunology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Knockout
  • Protein Glutamine gamma Glutamyltransferase 2
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology*
  • SARS-CoV-2 / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Transglutaminases / genetics
  • Transglutaminases / immunology*

Substances

  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Membrane Proteins
  • Sting1 protein, mouse
  • Interferon-beta
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases
  • GTP-Binding Proteins