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
Affiliations
Yilei Ma
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; Corresponding author
Ru Zhao
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
Hui Guo
Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Qingchao Tong
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
Wallace Y. Langdon
School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
Weiwei Liu
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Jun Zhang
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; Corresponding author
Jian Zhang
Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA; Corresponding author
Summary: 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.
