Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation
Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation
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DOI：
10.1038/ni.3008
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发表时间：
2014-11-01
影响因子：
30.5
通讯作者：
Heissmeyer, Vigo
中科院分区：
文献类型：
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作者：
Jeltsch, Katharina M.;Hu, Desheng;Heissmeyer, Vigo
由滤泡辅助性T细胞（T-FH细胞）积累引起的体液自身免疫与编码RNA结合蛋白roquin-1的基因突变有关。在这里，我们发现缺乏roquin的T细胞在肺中引起病理学，并在肺中积累为辅助T细胞的T（H）17亚群的细胞。Roquin抑制T（H）17细胞分化，并与核糖核酸内切酶regnase-1共同作用抑制编码T（H）17细胞促进因子IL-6、ICOS、c-Rel、IRF 4、I kappa BNS和I kappa B zeta的靶mRNA。这种合作需要通过roquin结合RNA和regnase-1的核酸酶活性。在T细胞抗原受体（TCR）识别抗原后，roquin和regnase-1蛋白被paracaspase MALT 1裂解。因此，该途径通过经由转录后阻遏物的分级失活和靶的差异去阻遏来翻译TCR信号强度以增强T（H）17分化而充当“变阻器”。
Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T-FH cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell promoting factors IL-6, ICOS, c-Rel, IRF4, I kappa BNS and I kappa B zeta. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T(H)17 differentiation.