Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation.
Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation.
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磷酸化状态确定SMAD2/SMAD3作为Th17分化中STAT3辅因子的相对功能。
DOI：
10.1038/ncomms8600
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发表时间：
2015-07-21
影响因子：
16.6
通讯作者：
Mamura M
中科院分区：
文献类型：
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作者：
Yoon JH;Sudo K;Kuroda M;Kato M;Lee IK;Han JS;Nakae S;Imamura T;Kim J;Ju JH;Kim DK;Matsuzaki K;Weinstein M;Matsumoto I;Sumida T;Mamura M
转化生长因子-β (TGF-β) 和白介素-6 (IL-6) 是诱导产生 IL-17 的 CD4+ T 辅助细胞 (TH17) 的关键细胞因子；然而，它们的信号网络在很大程度上仍然未知。在这里，我们展示了高度同源的TGF-β受体调节的Smads（R-Smads）：Smad2和Smad3分别作为STAT3的共激活子和共阻遏物，相反地修饰STAT3诱导的IL-17A和视黄酸受体相关孤儿核受体（由Rorc编码的RORγt）的转录。 Smad2 接头在丝氨酸 255 残基处被细胞外信号调节激酶 (ERK) 磷酸化，与 STAT3 和 p300 相互作用以反式激活，而羧基末端未磷酸化的 Smad3 与 STAT3 和活化 STAT3 的蛋白抑制剂 (PIAS3) 相互作用，抑制 Rorc 和 Il17a 基因。我们的工作揭示了 TH17 分化中不依赖于羧基末端磷酸化的非经典 R-Smad-STAT3 信号网络。 TGF-β 和 IL-6 是介导产生 IL-17 的 CD4+ T 辅助细胞 (TH17) 分化的重要细胞因子。在这里，尹等人。提供了对该过程的更多见解，并描述了 TGFβ 信号中间体 Smad2 和 Smad3 作为 STAT3 辅助因子在 Th17 分化中的相反作用。
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. TGF-ß and IL-6 are the essential cytokines for mediating the differentiation of IL-17-producing CD4+ T helper cells (TH17). Here, Yoon et al. provide more insights into this process and describe the opposing roles of TGFß-signalling intermediates Smad2 and Smad3 as STAT3 cofactors in Th17 differentiation.