Pellino3, a novel member of the Pellino protein family, promotes activation of c-Jun and Elk-1 and may act as a scaffolding protein.

Toll-like receptors and the IL-1R are part of the innate immune response aimed at mobilizing defense mechanisms in response to infections or injury. These receptors can initiate common intracellular signaling cascades. One intermediate component in these signaling cascades is Pellino, which was first identified in Drosophila and shown to interact with IL-1R-associated kinase. Two homologues, Pellino1 and Pellino2, have been identified in mammals. A novel member of the Pellino protein family has been identified and named Pellino3. Pellino3 shares 84 and 85% amino acid identity with Pellino1 and Pellino2, respectively. Two alternatively spliced Pellino3 mRNAs, Pellino3a and Pellino3b, are widely expressed. Pellino3 physically interacts with IL-1R-associated kinase-1, TNF receptor-associated factor-6, TGF-beta-activated kinase-1, and NF-kappaB-inducing kinase in an IL-1-dependent manner, suggesting that it plays a role as a scaffolding protein. In reporter assays Pellino3 leads to activation of c-Jun and Elk-1, but not NF-kappaB. Pellino3 also leads to activation of c-Jun N-terminal kinase. These data suggest that Pellino3 plays an important role in the innate immune response.