Opposing effects of Arkadia and Smurf on TGFbeta1-induced IgA isotype expression.
TGF-beta1 induces Ig germ-line alpha (GLalpha) 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 TGFbeta1-induced IgA CSR. We found that over-expression of Smurf1 and Smurf2 decreased TGFbeta1-induced GLalpha 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 GLalpha promoter activities, suggesting that the Smurfs can down-regulate the major TGF-beta1 signaling pathway and decrease GLalpha 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 TGFbeta1-induced IgA secretion. Conversely over-expression of Arkadia abolished the inhibitory effect of Smad7 on TGFbeta1-induced GLT(alpha) expression and IgA secretion. Similar results were obtained in the presence of over-expressed Smad7 and Smurf1. These results indicate that Arkadia can amplify TGFbeta1-induced IgA CSR by degrading Smad7, which interacts with Smurf1. We conclude that Smurf and Arkadia have opposite roles in the regulation of TGFbeta1-induced IgA isotype expression.
Choi
Seo-Hyun
SH
Department of Molecular Bioscience, School of Bioscience and Biotechnology, Kangwon National University, Chunchon 200-701, Korea.
Seo
Goo-Young
GY
Nam
Eun-Hee
EH
Jeon
Seong-Hyun
SH
Kim
Hyun-A
HA
Park
Jae-Bong
JB
Kim
Pyeung-Hyeun
PH
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D007070:Immunoglobulin A / Q000235:genetics*; D051379:Mice; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D007070:Immunoglobulin A; D012333:RNA, Messenger; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases