内部收益率3
坦克结合激酶1
刺
先天免疫系统
细胞生物学
生物
组织谷氨酰胺转胺酶
免疫学
免疫系统
信号转导
酶
生物化学
蛋白激酶C
丝裂原活化蛋白激酶激酶
工程类
航空航天工程
作者
Luca Occhigrossi,Federica Rossin,Manuela D’Eletto,Maria Grazia Farrace,Fabiola Ciccosanti,Linda Petrone,Alessandra Sacchi,Roberta Nardacci,Laura Falasca,Franca Del Nonno,Ivana Palucci,Е. М. Смирнов,Nick A. Barlev,Chiara Agrati,Delia Goletti,Giovanni Delogu,Gian María Fimia,Mauro Piacentini
出处
期刊:Journal of Immunology
[American Association of Immunologists]
日期:2021-05-03
卷期号:206 (10): 2420-2429
被引量:21
标识
DOI:10.4049/jimmunol.2001122
摘要
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.
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