题目：Cytosolic sensing of bacteria and bacterial virulence.

报告人：Feng Shao, Ph.D.

National Institute of Biological Sciences, Beijing

时间：2014-10-30（周四），13:00-14:00pm

地点：北京大学新生物楼邓祐才报告厅

联系人：生命科学联合中心， 方敏

Canonical inflammasomes are large cytoplasmic complexes that mediate caspase-1 activation, cytokine maturation and macrophage inflammatory death. We identify the NAIP family of NOD-like proteins (NLRs) that are inflammasome receptors for various bacterial products including flagellin and also the needle and rod subunit of bacterial toxin-injecting type III secretion system (T3SS) Ligation of the NAIPs by the corresponding ligands promotes their physical association with another NLR protein NLRC4, resulting in caspase-1 activation and anti-bacteria defense. We also discover that Pyrin, encoded by the familial Mediterranean fever disease gene MEFV, forms an inflammasome complex in response to bacterial modifications and inactivation of host Rho proteins. These include glucosylation by Clostridium difficile cytotoxin TcdB, adenylylation by FIC-domain bacterial effectors, ADP-ribosylation by C. botulinum C3 toxin and deamidation by B. cenocepacia, which all occur in the switch I region in Rho-subfamily GTPases. Loss of the Pyrin inflammasome causes elevated intra-macrophage growth of B. cenocepacia and diminished lung inflammation in mice. The NAIP and Pyrin inflammasome pathways serve as a mechanism for distinguishing pathogenic bacteria from non-pathogenic ones such as commensals. Lastly but most importantly, we demonstrate that inflammatory caspases including caspase-4/5 in human and caspase-11 in mice are cytosolic innate immune receptors for bacterial LPS (endotoxin). LPS directly binds to these caspases, leading to their oligomerization and catalytic activation and eventually necrotic cell death. Caspase-4/5/11-mediated non-canonical inflammasome activation plays a critical role in sepsis and septic shock, providing an attractive new target for anti-sepsis drug development.