TMEM173 Drives Lethal Coagulation in Sepsis

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

doi:10.1016/j.chom.2020.02.004

TMEM173 Drives Lethal Coagulation in Sepsis

Cell Host Microbe. 2020 Apr 8;27(4):556-570.e6. doi: 10.1016/j.chom.2020.02.004. Epub 2020 Mar 5.

Authors

Hui Zhang¹, Ling Zeng², Min Xie¹, Jiao Liu³, Borong Zhou³, Runliu Wu⁴, Lizhi Cao¹, Guido Kroemer⁵, Haichao Wang⁶, Timothy R Billiar⁷, Herbert J Zeh⁴, Rui Kang⁴, Jianxin Jiang⁸, Yan Yu⁹, Daolin Tang¹⁰

Affiliations

¹ Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
² Wound Trauma Medical Center, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China.
³ The Third Affiliated Hospital, Protein Modification and Degradation Lab of Guangzhou and Guangdong, Guangzhou Medical University, Guang Zhou, Guangdong 510600, China.
⁴ Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, China; Department of Women's and Children's Health, Karolinska University Hospital, 17176 Stockholm, Sweden.
⁶ Laboratory of Emergency Medicine, North Shore University Hospital and the Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
⁷ Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
⁸ Wound Trauma Medical Center, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. Electronic address: jiangjx@cta.cq.cn.
⁹ Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: xyyuyan@qq.com.
¹⁰ The Third Affiliated Hospital, Protein Modification and Degradation Lab of Guangzhou and Guangdong, Guangzhou Medical University, Guang Zhou, Guangdong 510600, China; Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: daolin.tang@utsouthwestern.edu.

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.

Keywords: ER stress; GSDMD; STING; TMEM173; calcium; coagulation; inflammasome; pyroptosis; sepsis; tissue factor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bacterial Infections
Blood Coagulation*
Calcium / metabolism
Disease Models, Animal
Humans
Inflammasomes
Intracellular Signaling Peptides and Proteins / metabolism
Macrophages / metabolism
Macrophages / pathology
Membrane Proteins / metabolism*
Mice
Monocytes
Phosphate-Binding Proteins / metabolism
Pyroptosis
Sepsis* / metabolism
Sepsis* / mortality
Signal Transduction
THP-1 Cells

Substances

GSDMD protein, human
Gsdmd protein, mouse
Inflammasomes
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Phosphate-Binding Proteins
STING1 protein, human
Sting1 protein, mouse
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding