Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation

Jeong-Hwan Yoon, Katsuko Sudo, Masahiko Kuroda, Mitsuyasu Kato, In-Kyu Lee, Jin Soo Han, Susumu Nakae, Takeshi Imamura, Juryun Kim, Ji Hyeon Ju, Dae-Kee Kim, Koichi Matsuzaki, Michael Weinstein, Isao Matsumoto, Takayuki Sumida and Mizuko Mamura ()
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Jeong-Hwan Yoon: Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba
Katsuko Sudo: Animal Research Center, Tokyo Medical University
Masahiko Kuroda: Tokyo Medical University
Mitsuyasu Kato: Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba
In-Kyu Lee: Kyungpook National University School of Medicine
Jin Soo Han: Institute for the 3Rs, College of Veterinary Medicine, Konkuk University
Susumu Nakae: Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, University of Tokyo
Takeshi Imamura: Graduate School of Medicine, Ehime University, Shitsukawa
Juryun Kim: Catholic University of Korea
Ji Hyeon Ju: Catholic University of Korea
Dae-Kee Kim: College of Pharmacy, Ewha Womans University
Koichi Matsuzaki: Kansai Medical University
Michael Weinstein: Ohio State University
Isao Matsumoto: University of Tsukuba
Takayuki Sumida: University of Tsukuba
Mizuko Mamura: Tokyo Medical University

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract Transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) are the pivotal cytokines to induce IL-17-producing CD4+ T helper cells (TH17); yet their signalling network remains largely unknown. Here we show that the highly homologous TGF-β receptor-regulated Smads (R-Smads): Smad2 and Smad3 oppositely modify STAT3-induced transcription of IL-17A and retinoic acid receptor-related orphan nuclear receptor, RORγt encoded by Rorc, by acting as a co-activator and co-repressor of STAT3, respectively. Smad2 linker phosphorylated by extracellular signal-regulated kinase (ERK) at the serine 255 residue interacts with STAT3 and p300 to transactivate, whereas carboxy-terminal unphosphorylated Smad3 interacts with STAT3 and protein inhibitor of activated STAT3 (PIAS3) to repress the Rorc and Il17a genes. Our work uncovers carboxy-terminal phosphorylation-independent noncanonical R-Smad–STAT3 signalling network in TH17 differentiation.

Date: 2015
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DOI: 10.1038/ncomms8600

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