Cytosolic LPS-induced caspase-11 oligomerization and activation is regulated by extended synaptotagmin 1

Yilei Ma; Ru Zhao; Hui Guo; Qingchao Tong; Wallace Y Langdon; Weiwei Liu; Jun Zhang; Jian Zhang

doi:10.1016/j.celrep.2023.112726

Cytosolic LPS-induced caspase-11 oligomerization and activation is regulated by extended synaptotagmin 1

Cell Rep. 2023 Jul 25;42(7):112726. doi: 10.1016/j.celrep.2023.112726. Epub 2023 Jul 1.

Authors

Yilei Ma¹, Ru Zhao², Hui Guo³, Qingchao Tong², Wallace Y Langdon⁴, Weiwei Liu⁵, Jun Zhang⁶, Jian Zhang⁷

Affiliations

¹ Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China; Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA; Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China. Electronic address: [email protected].
² Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China; Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China.
³ Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
⁴ School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.
⁵ Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA.
⁶ Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China; Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China. Electronic address: [email protected].
⁷ Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: [email protected].

Abstract

Caspase-11 (Casp-11) is known to induce pyroptosis and defends against cytosol-invading bacterial pathogens, but its regulation remains poorly defined. Here, we identified extended synaptotagmin 1 (E-Syt1), an endoplasmic reticulum protein, as a key regulator of Casp-11 oligomerization and activation. Macrophages lacking E-Syt1 exhibited reduced production of interleukin-1β (IL-1β) and impaired pyroptosis upon cytosolic lipopolysaccharide (LPS) delivery and cytosol-invasive bacterial infection. Moreover, cleavage of Casp-11 and its downstream substrate gasdermin D were significantly diminished in ESyt1^-/- macrophages. Upon LPS stimulation, E-Syt1 underwent oligomerization and bound to the p30 domain of Casp-11 via its synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain. E-Syt1 oligomerization and its interaction with Casp-11 facilitated Casp-11 oligomerization and activation. Notably, ESyt1^-/- mice were susceptible to infection by cytosol-invading bacteria Burkholderia thailandensis while being resistant to LPS-induced endotoxemia. These findings collectively suggest that E-Syt1 may serve as a platform for Casp-11 oligomerization and activation upon cytosolic LPS sensing.

Keywords: CP: Cell biology; CP: Immunology; E-Syt1; caspase-11; endotoxemia; host defense; oligomerization; pyroptosis.

Publication types

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

MeSH terms

Animals
Caspase 1 / metabolism
Caspases* / metabolism
Cytosol / metabolism
Inflammasomes / metabolism
Lipopolysaccharides* / metabolism
Lipopolysaccharides* / pharmacology
Macrophages / metabolism
Mice
Synaptotagmin I / metabolism

Substances

Caspase 1
Caspases
Inflammasomes
Lipopolysaccharides
Synaptotagmin I
Syt1 protein, mouse
Casp4 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding