Abstract
Canonical inflammasomes are large cytoplasmic complexes that mediate caspase-1 activation, cytokine maturation and macrophage inflammatory death. The speaker and his research group identify the NAIP family of NOD-like proteins (NLRs) that are inflammasome receptors for various bacterial products. In mice, NAIP5 directly recognizes flagellin while NAIP1 and NAIP2 are receptors for the needle and rod subunit of bacterial toxin-injecting type III secretion system (T3SS), respectively. Human NAIP (hNAIP) also recognizes the T3SS needle protein derived from a wide range of bacterial pathogens. 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. They also discover that Pyrin, encoded by the familial Mediterranean fever disease gene MEFV, forms an inflammasome complex in response to bacteria or bacterial toxin-induced inactivating modifications 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 as well as 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, they demonstrate that inflammatory caspases including caspase-4/5 in human and caspase-11 in mice are cytosolic innate immune receptors for bacterial LPS (also known as 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 in response to cytosolic LPS plays a critical role in sepsis and septic shock, providing an attractive new target for anti-sepsis drug development.
About the speaker
Dr Feng Shao received his PhD in Biological Chemistry from the University of Michigan Medical School in 2003. He had been postdoctoral fellow at the University of California at San Diego and Harvard Medical School. He joined the National Institute of Biological Sciences, Beijing in 2005, and is currently Investigator and Associate Director of the Institute.
Dr Shao's research interests focus on studying molecular mechanisms of bacterial infection and host innate immunity defense. He is taking a combination of biochemical, structural, genetic, and cell biological approaches to reveal novel biochemical mechanisms underlying bacterial virulence and host innate immunity.
Dr Shao received numerous awards including the Roche Chinese Young Investigator Award, the Promega Award for Biochemistry, the CBIS Young Investigator Award, the Protein Science Young Investigator Award and HHMI International Early Career Award, etc.
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