We have identified a new functional transmembrane receptor, LRRC19 (leucine-rich repeat containing 19), that belongs to the LRR protein family. LRRC19's central core has four analogous LRR repeating modules in a juxtaposed array and a casein kinase (CK2) phosphorylation site in the cytoplasmic domain. LRRC19 mRNA was found in the kidney, spleen and intestine of adult mice using both RT-PCR and in situ hybridization. LRRC19 does not contain a cytoplasmic Toll/IL-1 receptor (TIR) domain but was able to activate NF-kappaB and induce production of proinflammatory cytokines. LRRC19 shares a close evolutionary relationship with multiple Toll-like receptors (TLRs), especially TLR3. Importantly, the TLR3 ligand, as well as other TLR ligands, significantly promoted the expression of proinflammatory cytokines and the activation of NF-kappaB by LRRC19. Thus, LRRC19 may play an important role in inducing innate immune responses in certain tissues such as the kidney.