第726回 生医研セミナー(多階層生体防御システム研究拠点)
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演題
Pyroptosis in anti-bacterial immunity: sensing & execution
演者
Dr. Feng Shao
National Institute of Biological Sciences,Beijing
日時
2016年12月8日（木） Dec. 8(Thu), 2016
10：00 ～11：00
場所
病院キャンパス内 総合研究棟 1階 105号室
以下の地図の1番です。
（https://www.kyushu-u.ac.jp/f/28545/hospital_jp.pdf）
Room 105, 1F, Biomedical Research Station
No.1 on the following linked map.
（https://www.kyushu-u.ac.jp/f/28551/hospital_en.pdf）
要 旨
Inflammatory caspases (caspase-1, 4, 5 and 11) are critical for cytosolic defenses against bacterial infections. Caspase-1 is activated by the canonical inflammasome complex. We identify the NAIP family of NLR proteinsas inflammasome receptors for bacterial flagellin and type III secretion apparatus. Pyrin, encoded by the familial Mediterranean fever disease gene,forms a canonical inflammasome upon bacterial modifications/inactivation of host Rho GTPases. We also discover that human caspase-4/5 and murine caspase-11 are receptors for cytosolic LPS, critical for anti-bacterial defense and also septic shock. Common to inflammatory caspases activation is pyroptosis, a programmed necrotic cell death. Using genome-wide CRISPR/Cas9
screens, we identify gasdermin D (GSDMD) as the pyroptosis substrate for inflammatory caspases. GSDMD contains a functionally important gasdermin-N domain conserved in the gasdermin family. The gasdermin-N domains of GSDMD as well as other gasdermins can bind membrane lipids, phosphoinositides and cardiolipin, and exhibit membrane-disrupting cytotoxicity in both mammalian cells and bacteria. Purified gasdermin-N efficiently lyses the liposomes and
forms pores on the membrane. Most gasdermin pores have an inner diameter of 10～14 nm with 16 symmetric protomers. Crystal structure shows an autoinhibited two-domain architecture in the gasdermin family. The liposome-leakage and pore-forming activity of gasdermin-N is required for
pyroptosis. These findings reveal the mechanism for pyroptosis and provide insights into the roles of the gasdermin family in necrosis, immunity and diseases.
References
Ding, et al. Nature 2016
Shi, et al. Nature 2015
Shi, et al. Nature 2014
Xu, et al. Nature 2014
Li, et al. Nature 2013
連絡先
生体防御医学研究所 免疫制御学分野
山崎 晶 092(642)4614