Recognition of microbes by host cells is mediated in part by Toll-like receptors (TLRs) that are expressed primarily at the cell surface of immune cells. Mounting evidence indicate that host cells can also sense bacterial components in the cytosol but the cytosolic recognition system remains poorly understood. Recent studies have identified a large family of cytosolic proteins (named NODs) that has been implicated in the detection of bacterial components in the cytosol. Mammalian NODs contain remarkable structural homology to plant disease-resistance gene products that mediate protective immunity against invading pathogens. Two members of the NOD protein family, NOD1 and NOD2, detect conserved structures derived from bacterial peptidoglycan and upon activation activate NF-kappaB leading to the secretion of pro-inflammatory cytokines/chemokines. Thus, NOD family members appear to act as cytosolic receptors for microbial components and upon activation they induce inflammatory pathways against invading pathogens. The importance of the NOD family of proteins in inflammation has been recently revealed by the discovery that several inflammatory diseases are associated with mutations in NOD genes including NOD2 and Cryopyrin. Ipaf is another NOD family member highly related to NOD1 and NOD2. Like the latter proteins, Ipaf contains an N-terminal caspase-recruitment domain (CARD), centrally located nucleotide-binding oligomerization domain (NOD) and C-terminal leucine-rich repeats (LRRs). We and other investigators have provided evidence that Ipaf is involved in interleukin-1beta (IL-1beta) processing, NF-kappaB activation and apoptosis through interactions with the adaptor molecule ASC and caspase-1. Our hypothesis is that Ipaf recognizes a conserved bacterial structure and participates in a host defense pathway through the induction of proinflammatory activities including IL-1beta production.
The aim of this proposal is to provide a better understanding of the molecular mechanisms and physiological role of Ipaf in responses to inflammatory stimuli and infectious agents. Biochemical, genetic, and cellular approaches will be employed for gaining a better understanding of the function and signaling pathway mediated by Ipaf. The studies proposed may provide novel insight into the physiological role of the Ipaf signaling pathway in inflammation and host defense against pathogenic bacteria.
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