Peixing Wan, Swati Choksi, Yeon-Ji Park, Xin Chen, Jiong Yan, Sahar Foroutannejad, Zhaoshan Liu, Jichun Chen, Ross Lake, Chengyu Liu, Zheng-Gang Liu
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Soluble tissue factor generated by necroptosis-triggered shedding is responsible for thrombosis
Tissue factor (TF) is a cell surface protein critical for normal hemostasis and pathological thrombosis. Necroptosis is a form of regulated necrosis associated with different diseases. Here, we reported the identification of the first functional soluble tissue factor (sTF) in mediating blood coagulation, shed from the membrane full-length TF (flTF) by proteases, ADAMs, during necroptosis. By generating sTF-specific antibody and transgenic mice carrying knockin mutations at the ADAM cleavage site of TF (T211V212 mutated to E211E212), we demonstrated that this sTF is responsible for necroptosis-related thrombosis in inflammation and viral infection mouse models. Importantly, we showed that eliminating necroptosis or the cleavage of the flTF blocked the production of sTF and prevented thrombosis in mice. We also detected sTF in the plasma of human COVID-19 patients and showed that SARS-CoV-2 pseudovirus induced sTF production. Our findings demonstrated that the sTF plays a major role in thrombosis under necroptosis-related pathological conditions and provided a diagnostic marker and potential therapies for treating thrombosis without affecting hemostasis.
期刊介绍:
Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.