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, Mizuko Mamura

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


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.

Original languageEnglish
Article number7600
JournalNature Communications
StatePublished - 21 Jul 2015

Bibliographical note

Funding Information:
We thank C. Deng (National Institutes of Health, USA) for Smad3+/− mice; M. Yamamoto (Tohoku University, Japan) for Mx-1Cre Tg mice; A. Nakao (University of Yamanashi, Japan), L. Wakefield R. Horai, H. Yamane (National Institutes of Health, USA), H. Yanai, H. Negishi, J. Nishio, H. Ikushima, T. Taniguchi (University of Tokyo, Japan) and M. Sporn (Dartmouth Medical School, USA) for helpful discussions and critical reading of the manuscript; B. Oh (Gachon University, Korea) for assistance in designing some luciferase constructs. This work was supported by Mochida Memorial Foundation for Medical and Pharmaceutical Research, Research Resident Grant by The Association for Preventive Medicine of Japan, Research Grant by Japan Rheumatism Foundation, a grant from the Kwang-dong Pharmaceutical Co., Bio Technology R&D Program, Republic of Korea (20090081756), Basic Science Research Program through the National Research Foundation of Korea (NRF-2012R1A1A3015334 and NRF-2015R1A1A3A04001051), a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A092258), a grant of the Korea Health technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea. (Grant Number: A111345) and the Pioneer Research Center Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (2015-001937 and 2015-001923).

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