2008年6月25日,来自韩国Korea Advanced Institute of Science and Technology化学系的副教授Jie-Oh Lee博士访问研究所并做学术讲座,

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TLR4 and MD-2 form a heterodimer that recognizes LPS from Gram negative bacteria. Eritoran is an analogue of LPS that antagonizes its activity by binding to the TLR4-MD2 complex. We determined the structure of the full-length ectodomain of mouse TLR4 and MD-2 complex . We also produced a series of hybrids of human TLR4 and hagfish VLR and determined their structures with and without bound MD-2 and Eritoran. TLR4 is an atypical member of the LRR family and is composed ofsheet of the central domainbN-terminal, central and C-terminal domains. Theshows unusually small radii and large twist angles. MD-2 binds to the concave surface of the N-terminal and central domains. The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4, we propose a model of TLR4-MD-2 dimerization induced by LPS.

报告题目:Innate immunity to cytosolic bacteria: pyroptosis and beyond 报 告 人:邵 峰 院士(北京生命科学研究所)主 持 人:廉哲雄 教授报告时间:2019年3月14日15:00报告地点:大学城校区B2-335会议室欢迎广大师生参加!医学院2019年2月27日报告摘要:Lipopolysaccharide , the major cell-wall component of Gram-negative bacteria, is long known to be sensed by the plasma membrane-bound TLR4 receptor. Ligation of TLR4 by the lipid A of LPS stimulates NF-κB and IRF-mediated inflammatory cytokine production. Recently, we showed that caspase-11, 4 and 5 are cytosolic immune receptors for LPS and activated by direct binding to its lipid A part. Like caspase-1 activation by the canonical inflammasome, caspase-11/4/5 activation induces pyroptosis, both of which are critical for antibacterial defense and development of immunological diseases. Caspase-11/4/5 and caspase-1 cleave Gasdermin D to release the autoinhibition of its N-terminal domain that bears an intrinsic pore-forming activity for executing pyroptotic cell death.Gsdmd-/-mice are susceptible to various bacterial infections and also resist LPS-induced septic shock. GSDMD belongs to a large Gasdermin family sharing the pore-forming domain. Another family member GSDME whose expression is silenced in most cancer cells, is activated by caspase-3 cleavage; inflammatory damages caused by GSDME-mediated pyroptosis is the major determinant for the toxicity of those DNA-damaging chemotherapy drugs. Lastly, we discover that ADP-heptose, the precursor for LPS inner core oligosaccharide, is recognized in host cytosol by a novel kinase receptor ALPK1. Like lipid A-activated TLR4, ADP-heptose-activated ALPK1 potently stimulates NF-κB-dependent inflammatory responses both in cells and mice. These findings shift the paradigm of immune sensing of LPS and antibacterial defense, and open several new areas of research on innate immunity and pyroptosis-mediated inflammation. The cell-entry property of ADP-heptose also suggests a new way of modulating immune responses in mammals.报告人简介:邵峰博士1996年毕业于北京大学技术物理系,1999年于中科院生物物理所获得硕士学位,2003年美国密西根大学生物化学系获得博士学位,现为北京生命科学研究所资深研究员、科研副所长。邵峰博士长期研究病原细菌和宿主相互作用机理,在致病菌毒力机制以及抗细菌天然免疫方向均取得系列重要原创性发现:包括发现细菌内毒素、鞭毛以及病原菌三型分泌系统的胞内天然免疫受体(组装形成炎症小体复合物),进而揭示和阐明了这些受体下游的炎性caspase通过剪切活化Gasdermin D蛋白诱导细胞焦亡的确切分子机制;这些发现为败血症药物和细菌疫苗的研发提供了新的理论基础,其中有关Gasdermin家族蛋白的鉴定和机制的阐述也将细胞焦亡的概念重新定义为由Gasdermin家族介导的细胞程序性坏死。邵峰博士已发表学术论文70多篇,总引用9,000多次,2005年回国后以通讯作者在《自然》、《科学》和《细胞》三大杂志发表研究论文13篇;获得多项国际和国内重要奖项,包括周光召杰出青年基础科学奖、HHMI国际青年科学家奖、国际蛋白质学会鄂文西格青年科学家奖、吴阶平-保罗杨森基础医学奖以及何梁何利基金科学与技术奖等,入选北京市海外高层次人才工程、国家百千万人才工程、首届“北京学者”以及国家万人计划,为享受国务院特殊津贴专家,2015年当选为中科院院士和EMBO的外籍成员,2016年当选为美国微生物学院院士。

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