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

被引：115

作者：

Yoon, Jeong-Hwan ^{[1
,2
,3
,4
]}

Sudo, Katsuko ^{[5
]}

Kuroda, Masahiko ^{[3
]}

Kato, Mitsuyasu ^{[1
,2
]}

Lee, In-Kyu ^{[4
]}

Han, Jin Soo ^{[6
]}

Nakae, Susumu ^{[7
]}

Imamura, Takeshi ^{[8
]}

Kim, Juryun ^{[9
]}

Ju, Ji Hyeon ^{[9
]}

Kim, Dae-Kee ^{[10
]}

Matsuzaki, Koichi ^{[11
]}

Weinstein, Michael ^{[12
]}

Matsumoto, Isao ^{[13
]}

Sumida, Takayuki ^{[13
]}

Mamura, Mizuko ^{[3
,4
]}

机构：

[1] Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Expt Pathol, Tsukuba, Ibaraki 3058575, Japan

[2] Univ Tsukuba, Fac Med, Tsukuba, Ibaraki 3058575, Japan

[3] Tokyo Med Univ, Dept Mol Pathol, Shinjuku Ku, Tokyo 1608402, Japan

[4] Kyungpook Natl Univ, Sch Med, Dept Internal Med, Daegu 700721, South Korea

[5] Tokyo Med Univ, Anim Res Ctr, Shinjuku Ku, Tokyo 1608402, Japan

[6] Konkuk Univ, Coll Vet Med, Inst 3Rs, Dept Lab Anim Med, Seoul 143701, South Korea

[7] Univ Tokyo, Inst Med Sci, Ctr Expt Med & Syst Biol, Lab Syst Biol,Minato Ku, Tokyo 1088639, Japan

[8] Ehime Univ, Grad Sch Med, Dept Mol Med Pathogenesis, Toon, Ehime 7910295, Japan

[9] Catholic Univ Korea, Dept Rheumatol, Seoul 137701, South Korea

[10] Ewha Womans Univ, Coll Pharm, Seoul 120750, South Korea

[11] Kansai Med Univ, Dept Gastroenterol & Hepatol, Moriguchi, Osaka 5708506, Japan

[12] Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA

[13] Univ Tsukuba, Dept Internal Med, Tsukuba, Ibaraki 3058575, Japan

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

新加坡国家研究基金会;

关键词：

COLLAGEN-INDUCED ARTHRITIS; TGF-BETA SUPERFAMILY; GROWTH-FACTOR-BETA; CELL DEVELOPMENT; SMAD; TH17; TRANSCRIPTION; IL-6; GENERATION; INHIBITION;

D O I：

10.1038/ncomms8600

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Transforming growth factor-beta (TGF-beta) and interleukin-6 (IL-6) are the pivotal cytokines to induce IL-17-producing CD4(+) T helper cells (T(H)17); yet their signalling network remains largely unknown. Here we show that the highly homologous TGF-beta receptor-regulated Smads (R-Smads): Smad2 and Smad3 oppositely modify STAT3-induced transcription of IL-17A and retinoic acid receptor-related orphan nuclear receptor, ROR gamma t 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 T(H)17 differentiation.

引用

页数：14

共 59 条

[31] Role of SMAD and Non-SMAD Signals in the Development of Th17 and Regulatory T Cells [J].