Opposing effects of arkadia and smurf on TGFβ1-induced IgA isotype expression

초록

TGF-beta 1 induces Ig germ-line a (GL alpha) 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 TGF beta 1-induced IgA CSR. We found that over-expression of Smurf1 and Smurf2 decreased TGF beta 1-induced GLa 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 GLa promoter activities, suggesting that the Smurfs can down-regulate the major TGF-beta 1 signaling pathway and decrease GLa gene expression. In parallel, the over-expressed Smurf1 decreased the expression of endogenous IgA CSR-predictive transcripts (GLT alpha, PST alpha, and CT alpha) and also TGFO-Induced IgA secretion. Conversely over-expression of Arkadia abolished the inhibitory effect of Smad7 on TGFPI-induced GLT, expression and IgA secretion. Similar results were obtained in the presence of overexpressed Smad7 and Smurf1. These results indicate that Arkadia can amplify TGF beta 1-induced IgA CSR by degrading Smad7, which interacts with Smurfl. We conclude that Smurf and Arkadia have opposite roles in the regulation of TGF beta 1-induced IgA isotype expression.

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