| First Author | Ma Y | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 7 | Pages | 112726 |
| PubMed ID | 37393619 | Mgi Jnum | J:337961 |
| Mgi Id | MGI:7508946 | Doi | 10.1016/j.celrep.2023.112726 |
| Citation | Ma Y, et al. (2023) Cytosolic LPS-induced caspase-11 oligomerization and activation is regulated by extended synaptotagmin 1. Cell Rep 42(7):112726 |
| abstractText | 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-1beta (IL-1beta) 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. |
