Innate immune sensing of pathogen-associated enzymatic activities

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Talk abstract:

Many immune responses are initiated through the recognition of pathogen associated molecular patterns (PAMPs), such as flagellin or bacterial lipopolysaccharide, by germline encoded receptors. While the mechanisms by which these receptors recognize PAMPs are well established, there is mounting evidence that the immune system is also able to recognize pathogen-associate activities. However, the molecular mechanisms by which the immune system can sense these pathogen-associated activities have remained unclear. To uncover such mechanisms, we have investigated how the NLRP1B inflammasome is able to recognize the enzymatic activity of the Bacillus anthracis lethal factor (LF) protease. Unexpectedly, we have found that cleavage of NLRP1B by LF leads to proteasomal degradation of NLRP1B. Degradation of NLRP1B leads to the release of an active fragment which self-oligomerizes, and recruits and activates caspase-1 to initiate a downstream inflammatory response. This model of activation further led us to identify a novel enzyme that activates NLRP1B, the secreted E3 ligase IpaH7.8 from Shigella flexneri. These results identify a novel unified mechanism through which the NLRP1B inflammasome is able to detect pathogen-associated enzymatic activities.