Regulation of caspase-1 activation by IQGAP1 during bacterial infection

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 DESCRIPTION (provided by applicant): Recognition of pathogens by host defenses and subsequent activation of caspase-1 is important to resolve bacterial infection. Despite this, pathogens have developed mechanisms to prevent activation of caspase-1 to ensure survival and replication. An example of such is the effector YopM, an important virulence determinant of pathogenic Yersinia. YopM inhibits activation of caspase-1, yet the molecular mechanisms underlying this process remain largely unknown. We recently identified the host scaffolding protein IQGAP1 as a novel binding partner of YopM and found IQGAP1 to be important for activation of caspase-1 in response to Yersinia infection. These findings suggest that YopM inhibits activation of caspase-1 through targeting of IQGAP1. Given the importance of caspase-1 activation for host protection, understanding how IQGAP1 regulates activation of caspase-1 along with how pathogens subvert this process could aid the development of therapeutic strategies to combat bacterial infections. To accomplish this goal, three aims have been developed. Aim 1 seeks to identify the role of IQGAP1 for host protection against Yersinia. Aim 2 will determine the molecular mechanism of how IQGAP1 regulates activation of caspase-1 and how YopM disrupts this process. Aim 3 focuses on the importance of IQGAP1 for activation of caspase-1 in response to Salmonella, which also possess an effector that targets IQGAP1. Accomplishing these aims will provide mechanistic insight on how IQGAP1 regulates activation of caspase-1 and will contribute to development of novel therapeutic strategies against infectious disease.