Regulation of caspase-1 activation by IQGAP1 during bacterial infection

 描述（由申请人提供）：宿主防御系统识别病原体并随后激活半胱天冬酶-1对于解决细菌感染非常重要。尽管如此，病原体已经开发出防止caspase-1激活的机制，以确保存活和复制。这样的一个例子是效应子YopM，致病性耶尔森氏菌的重要毒力决定因子。YopM抑制caspase-1的激活，但这一过程的分子机制仍然在很大程度上未知。我们最近确定了宿主支架蛋白IQGAP 1作为YopM的一种新的结合伴侣，并发现IQGAP 1对响应耶尔森氏菌感染的caspase-1的激活是重要的。这些发现表明，YopM通过靶向IQGAP 1抑制caspase-1的活化。鉴于caspase-1激活对宿主保护的重要性，了解IQGAP 1如何调节caspase-1的激活沿着病原体如何破坏这一过程可以帮助开发对抗细菌感染的治疗策略。为了实现这一目标，制定了三个目标。目的1旨在确定IQGAP 1对宿主保护耶尔森氏菌的作用。目的2将确定IQGAP 1如何调节caspase-1激活的分子机制以及YopM如何破坏这一过程。目标3重点关注IQGAP 1对于激活半胱天冬酶-1以响应沙门氏菌的重要性，沙门氏菌也具有靶向IQGAP 1的效应子。实现这些目标将提供关于IQGAP 1如何调节caspase-1活化的机制见解，并将有助于开发针对感染性疾病的新治疗策略。

 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.