TMEM173 Drives Lethal Coagulation in Sepsis.

Abstract	The discovery of TMEM173/STING-dependent innate immunity has recently provided guidance for the prevention and management of inflammatory disorders. Here, we show that myeloid TMEM173 occupies an essential role in regulating coagulation in bacterial infections through a mechanism independent of type I interferon response. Mechanistically, TMEM173 binding to ITPR1 controls calcium release from the endoplasmic reticulum in macrophages and monocytes. The TMEM173-dependent increase in cytosolic calcium drives Gasdermin D (GSDMD) cleavage and activation, which triggers the release of F3, the key initiator of blood coagulation. Genetic or pharmacological inhibition of the TMEM173-GSDMD-F3 pathway blocks systemic coagulation and improves animal survival in three models of sepsis (cecal ligation and puncture or bacteremia with Escherichia coli or Streptococcus pneumoniae infection). The upregulation of the TMEM173 pathway correlates with the severity of disseminated intravascular coagulation and mortality in patients with sepsis. Thus, TMEM173 is a key regulator of blood clotting during lethal bacterial infections.
Authors	Hui Zhang, Ling Zeng, Min Xie, Jiao Liu, Borong Zhou, Runliu Wu, Lizhi Cao, Guido Kroemer, Haichao Wang, Timothy R Billiar, Herbert J Zeh, Rui Kang, Jianxin Jiang, Yan Yu, Daolin Tang
Journal	Cell host & microbe (Cell Host Microbe) Vol. 27 Issue 4 Pg. 556-570.e6 (04 08 2020) ISSN: 1934-6069 [Electronic] United States
PMID	32142632 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2020 Elsevier Inc. All rights reserved.
Chemical References	GSDMD protein, human Gsdmd protein, mouse Inflammasomes Intracellular Signaling Peptides and Proteins Membrane Proteins Phosphate-Binding Proteins STING1 protein, human Sting1 protein, mouse Calcium
Topics	Animals Bacterial Infections Blood Coagulation Calcium (metabolism) Disease Models, Animal Humans Inflammasomes Intracellular Signaling Peptides and Proteins (metabolism) Macrophages (metabolism, pathology) Membrane Proteins (metabolism) Mice Monocytes Phosphate-Binding Proteins (metabolism) Pyroptosis Sepsis (metabolism, mortality) Signal Transduction THP-1 Cells

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