TGF-β1 induces Ig germ-line α (GLα) transcription and subsequent class switching recombination (CSR) to IgA. In the present study, we investigated the roles of two E3-ubiquitin ligases, Smurfs (HECT type) and Arkadia (RING finger type) on TGFβ1-induced IgA CSR. We found that over-expression of Smurf1 and Smurf2 decreased TGFβ1-induced GLα promoter activity and strengthened the inhibitory effect of Smad7 on the promoter activity. Further, over-expression of Smurf1 and Smurf2 decreased both Smad3/4-mediated and Runx3-mediated GLα promoter activities, suggesting that the Smurfs can down-regulate the major TGF-β1 signaling pathway and decrease GLα gene expression. In parallel, the over-expressed Smurf1 decreased the expression of endogenous IgA CSR-predictive transcripts (GLTα, PSTα, and CTα) and also TGFβ?1-induced IgA secretion. Conversely over-expression of Arkadia abolished the inhibitory effect of Smad7 on TGFβ1-induced GLT? expression and IgA secretion. Similar results were obtained in the presence of over-expressed Smad7 and Smurf1. These results indicate that Arkadia can amplify TGFβ1-induced IgA CSR by degrading Smad7, which interacts with Smurf1. We conclude that Smurf and Arkadia have opposite roles in the regulation of TGFβ1-induced IgA isotype expression.

Keywords: Arkadia, IgA, Smad7, Smurf, TGF-β1