Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan;
J Immunol. 2014 Feb 15;192(4):1547-57. doi: 10.4049/jimmunol.1300989. Epub 2014 Jan 8.
T cell activation is dependent upon phosphorylation of MAPKs, which play a critical role in the regulation of immune responses. Dual-specificity phosphatase 14 (DUSP14; also known as MKP6) is classified as a MAPK phosphatase. The in vivo functions of DUSP14 remain unclear. Thus, we generated DUSP14-deficient mice and characterized the roles of DUSP14 in T cell activation and immune responses. DUSP14 deficiency in T cells resulted in enhanced T cell proliferation and increased cytokine production upon T cell activation. DUSP14 directly interacted with TGF-β-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser(438), leading to TAB1-TAK1 complex inactivation in T cells. The phosphorylation levels of the TAB1-TAK1 complex and its downstream molecules, including JNK and IκB kinase, were enhanced in DUSP14-deficient T cells upon stimulation. The enhanced JNK and IκB kinase activation in DUSP14-deficient T cells was attenuated by TAB1 short hairpin RNA knockdown. Consistent with that, DUSP14-deficient mice exhibited enhanced immune responses and were more susceptible to experimental autoimmune encephalomyelitis induction. Thus, DUSP14 negatively regulates TCR signaling and immune responses by inhibiting TAB1 activation.
T 细胞的激活依赖于 MAPKs 的磷酸化，MAPKs 在免疫反应的调节中起着关键作用。双特异性磷酸酶 14（DUSP14；也称为 MKP6）被归类为 MAPK 磷酸酶。DUSP14 的体内功能尚不清楚。因此，我们生成了 DUSP14 缺陷型小鼠，并表征了 DUSP14 在 T 细胞激活和免疫反应中的作用。T 细胞中 DUSP14 的缺失导致 T 细胞增殖增强，T 细胞激活时细胞因子产生增加。DUSP14 直接与 TGF-β激活激酶 1（TAK1）结合蛋白 1（TAB1）相互作用，并使 TAB1 在 Ser（438）上脱磷酸化，导致 T 细胞中 TAB1-TAK1 复合物失活。在刺激下，DUSP14 缺陷型 T 细胞中 TAB1-TAK1 复合物及其下游分子（包括 JNK 和 IκB 激酶）的磷酸化水平增强。DUSP14 缺陷型 T 细胞中 JNK 和 IκB 激酶的激活增强被 TAB1 短发夹 RNA 敲低所减弱。与此一致的是，DUSP14 缺陷型小鼠表现出增强的免疫反应，并且更容易诱导实验性自身免疫性脑脊髓炎。因此，DUSP14 通过抑制 TAB1 激活来负调控 TCR 信号和免疫反应。
