NLRP12 REGULATES TLR2/DECTIN-1 FUNGAL RECEPTOR SIGNALING THROUGH ASSOCIATION WITH CARD9 (135.74)

Abstract

Abstract The NLR (nucleotide-binding domain, leucine-rich repeat) proteins are recently recognized as important intracellular regulators of host defense and immunity. One NLR gene, NLRP12/Monarch-1, has emerged as an important inhibitor of inflammatory gene expression in myeloid cells via regulation of TLRs and TNFR signal transduction. In contrast to its known role in regulating bacterial induced TLR activation of downstream genes, little is known about the role of NLRP12 in regulating the immune response to fungal pathogens. Here we show that NLRP12 modulates innate immune cellular responses to A. fumigatus by regulating TLR2/Dectin-1 fungal receptor signaling through its association with downstream signaling proteins CARD9 and Bcl10, but not Malt1. NLRP12, consisting of a pyrin, a nucleotide binding and a leucine rich repeat domain associates with the caspase recruitment domain containing proteins CARD9 and Bcl10 via the adaptor protein ASC. The most severe form of the NLRP12 disease associated mutant protein lacks the ability to associate with ASC, CARD9 and Bcl10 resulting in the lack of NLRP12's normal negative regulatory function. These data demonstrate the important role played by NLRP12 in modulating the innate immune response to fungal pathogens via its regulation of the TLR2/Dectin-1 induced CARD9 signaling pathway. This work was supported by NIH grants HL-30923 and HL-68072 (JRW), NIH COBRE grant RR020185 (RAC) a SERCEB award and funding from CCBVP to KLW.