Transglutaminase 2 regulates innate immunity by modulating the STING/TBK1/IRF3 axis

Detection of pathogen associated molecular patterns (PAMPs) by patternrecognition receptor (PRR) is an essential mechanism of innate immunity found in most organisms, as a first line of defence against pathogens. cGAS/STING pathway is the main signalling activated in the presence of both self and pathogen DNA, leading to Type I Interferon (IFN I) production to trigger immune response. In fact, following activation, IRF3 is phosphorylated on serine 396 by TBK1 and moved into the nucleus by promoting expression of IFN I. Previous work showed that Type 2 transglutaminase (TG2), a multifunctional enzyme, plays a key role during bacterial infection, although the mechanism remains understood. Here, we show that TG2 regulates the STING signalling affecting IRF3 phosphorylation state. In fact, in absence of TG2 we found an increase in interferon beta (IFNβ) production and downstream activation. Interestingly, proteomic analysis revealed that TG2 interacts with TBK1 affecting its interactome composition. Indeed, TG2 ablation facilitates the TBK1-IRF3 interaction, indicating an inhibitory effect on TBK1. Interestingly, SARS-CoV2 infection promotes an IFN I storm in the late stages of disease related to negative prognosis. Actually, we observed an increase in IFNβ production in bronchoalveolar lavage fluids from COVID-19 positive dead patients and, accordingly with our findings, we found that TG2 expression was dramatically decreased in the pneumocytes. Taken together these results suggest that TG2 plays a negative regulation on IFNβ response leading to attenuation of the infection response.