Junling Liu and Yanyan Xu’s group reports the mechanism of platelet STING in regulating sepsis-induced thrombosis
Source：Yanyan Xu
2023-07-13
On May 9, 2023, the Cell Press journal IMMUNITY published the article “STING activation in platelets aggravates septic thrombosis by enhancing platelet activation and granule secretion” led by Liu and Xu’s team at Shanghai Jiao Tong University School of Medicine. The study systematically revealed that STING, the DNA sensor, in platelets promoted their granule secretion, which led to subsequent septic thrombosis. Furthermore, this work identified STING-STXBP2 interaction as a potential target for sepsis intervention.
Sepsis is a severe systemic inflammatory response syndrome (SIRS) caused by bacterial infection. Septic patients are at a high risk of developing coagulation dysfunction and life-threatening disseminated intravascular coagulation (DIC). STING, an endoplasmic reticulum tethering and sensing protein, exerts inhibitory effects on bacterial infection upon activation by pathogenic microorganism-derived DNA. In this study, the researchers found that STING deficiency could suppress platelet activation, alleviate sepsis-induced intravascular thrombosis and NETosis, decrease the level of multiple organ dysfunction and enhance the survival rate in mice. The results provide a clear explanation for how STING played a critical role in granule secretion of platelets, NETosis and septic thrombosis.
The study systematically revealed the underlying mechanism of how STING interacted with STXBP2 and was involved in the assembly of SNARE complex and granule secretion in platelets, by which the level of SNARE complex assembly was suppressed upon deletion. In addition, sepsis-derived cGAMP promoted the binding of STING to STXBP2, thereby promoting the assembly of SNARE complex, granule secretion, platelet activation and subsequent septic thrombosis, which probably depended on the palmitoylation of STING. Moreover, through designing and screening corresponding peptides which suppressed the binding of STING to STXBP2, the peptide C-ST5 could inhibit platelet activation, platelet- driven NETosis, and sepsis-induced thrombosis. In conclusion, this work revealed the important role of STING in regulating platelet activation, suggesting that targeting the interaction between STING and STXBP2 may be a potential intervention for the treatment of septic thrombosis.
Yanyan Xu, Junling Liu, and Haojie Jiang from School of Medicine at Shanghai Jiao Tong University are co-corresponding authors of this work. Mina Yang and Haojie Jiang from School of Medicine at Shanghai Jiao Tong University are co-first authors. The work was funded by grants from the National Natural Science Foundation of China, National Key R&D Program of China and etc.
Article Links: https://www.cell.com/immunity/fulltext/S1074-7613(23)00089-4
Sepsis is a severe systemic inflammatory response syndrome (SIRS) caused by bacterial infection. Septic patients are at a high risk of developing coagulation dysfunction and life-threatening disseminated intravascular coagulation (DIC). STING, an endoplasmic reticulum tethering and sensing protein, exerts inhibitory effects on bacterial infection upon activation by pathogenic microorganism-derived DNA. In this study, the researchers found that STING deficiency could suppress platelet activation, alleviate sepsis-induced intravascular thrombosis and NETosis, decrease the level of multiple organ dysfunction and enhance the survival rate in mice. The results provide a clear explanation for how STING played a critical role in granule secretion of platelets, NETosis and septic thrombosis.
The study systematically revealed the underlying mechanism of how STING interacted with STXBP2 and was involved in the assembly of SNARE complex and granule secretion in platelets, by which the level of SNARE complex assembly was suppressed upon deletion. In addition, sepsis-derived cGAMP promoted the binding of STING to STXBP2, thereby promoting the assembly of SNARE complex, granule secretion, platelet activation and subsequent septic thrombosis, which probably depended on the palmitoylation of STING. Moreover, through designing and screening corresponding peptides which suppressed the binding of STING to STXBP2, the peptide C-ST5 could inhibit platelet activation, platelet- driven NETosis, and sepsis-induced thrombosis. In conclusion, this work revealed the important role of STING in regulating platelet activation, suggesting that targeting the interaction between STING and STXBP2 may be a potential intervention for the treatment of septic thrombosis.
Yanyan Xu, Junling Liu, and Haojie Jiang from School of Medicine at Shanghai Jiao Tong University are co-corresponding authors of this work. Mina Yang and Haojie Jiang from School of Medicine at Shanghai Jiao Tong University are co-first authors. The work was funded by grants from the National Natural Science Foundation of China, National Key R&D Program of China and etc.
Article Links: https://www.cell.com/immunity/fulltext/S1074-7613(23)00089-4
