Pellino3, a Novel Member of the Pellino Protein Family, Promotes Activation of c-Jun and Elk-1 and May Act as a Scaffolding Protein

Abstract

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-β-activated kinase-1, and NF-κB-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-κB. 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.

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

“…Three mammalian homologues (Pellino1, 2 and 3) have since been identified, with Pellino3 being expressed in two spliced forms [35][36][37][38][39]. Given that Drosophila Pellino was discovered based on its interaction with Pelle, mammalian Pellino proteins have been characterized by their potential to interact with IRAK molecules.…”

“…Given that Drosophila Pellino was discovered based on its interaction with Pelle, mammalian Pellino proteins have been characterized by their potential to interact with IRAK molecules. Overexpression studies have shown that mammalian Pellino proteins interact with both IRAK1 and IRAK4 [36,37,[40][41][42][43]. Furthermore, a yeast two-hybrid screen using IRAK4 as bait independently identified Pellino2 as a protein-binding partner [40].…”

“…Furthermore, a yeast two-hybrid screen using IRAK4 as bait independently identified Pellino2 as a protein-binding partner [40]. Under physiological conditions, the Pellino-IRAK interactions are likely to be dependent on prior TLR or IL-1R stimulation because endogenous IRAK-Pellino associations are not observed in resting cells but manifest in response to stimulation by IL-1 [33,[35][36][37]44] and LPS [44].…”

“…Some groups have shown that IRAK kinase activity is dispensable for IRAK-Pellino interactions [40,42,45]. However, two other groups propose that IRAK1-Pellino binding requires IRAK1 kinase activity [37,46], which is supported by the fact that IRAK1b, a naturally occurring alternative splice variant of IRAK1 that is kinase inactive, fails to interact with Pellino3 [37]. The basis to the opposing conclusions might be a result of interpretations being made exclusively on the basis of overexpression studies.…”

“…None of the Pellino proteins have been reported to interact with TLR or IL-1R complexes, however, one report indicates that IL-1 signalling can promote the interaction of overexpressed Pellino1 with MyD88 [44]. However, other reports have failed to detect any basal interactions between overexpressed MyD88 and Pellino proteins [37,47]. Many groups have described associations of each of the Pellino proteins with TRAF6 and these interactions are strongly promoted by IL-1R signalling [33,36,37,41,44,47].…”