Mechanisms of negative regulation of inflammasome activation
Carpentier, Samuel Jeffrey
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Pyroptosis is an inflammatory program of cell death that is coordinated by the assembly of macromolecular structures known as inflammasomes. Pathogenic Yersinia species have evolved specific mechanisms to inhibit inflammasome activation. We identified the C-terminus of Yersinia virulence effector YopM is required for YopM inhibition of caspase-1 recruitment to pre-inflammasomes. Additionally, we found efficient caspase-1 activation in foci and the appearance of active caspase-1 distributed throughout the cytoplasm are important aspects of the host immune response and antagonizing these processes are key for Yersinia pathogenesis. While inflammation can be beneficial in response to pathogens, excess inflammation is a serious health problem associated with organ damage resulting from infections, cancers, heart attacks, and strokes. However, host regulation of inflammasome activation is poorly understood. Through collaboration with the Hamerman lab we have identified a host protein, B-cell adaptor for PI3K (BCAP), involved in the regulation of inflammasome maturation. BCAP regulates inflammasome activation through interactions with the host inflammasome inhibitor Flightless-I. Mechanistically, BCAP delays the recruitment of caspase-1 to the forming inflammasome through its association with the caspase-1 pseudosubstrate inhibitor Flightless-1. Thus, we have identified an inhibitory pathway that regulates inflammasome activation and innate immune cell function.
- Microbiology