DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions.
DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions.
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DOI：
10.1038/nature16193
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发表时间：
2015-12-24
期刊：
影响因子：
64.8
通讯作者：
Littman DR
中科院分区：
文献类型：
--
作者：
Huang W;Thomas B;Flynn RA;Gavzy SJ;Wu L;Kim SV;Hall JA;Miraldi ER;Ng CP;Rigo F;Meadows S;Montoya NR;Herrera NG;Domingos AI;Rastinejad F;Myers RM;Fuller-Pace FV;Bonneau R;Chang HY;Acuto O;Littman DR
Th17 淋巴细胞可保护粘膜屏障免受感染，但也会导致多种慢性炎症性疾病。它们的分化由配体调节的核受体 RORγt 控制。我们鉴定出 DEAD-box RNA 解旋酶 DDX5 作为 RORγt 伴侣，协调选择性 Th17 基因的转录，并且是 Th17 介导的炎症病理学所必需的。令人惊讶的是，DDX5 与 RORγt 相互作用并共同激活其靶标的能力取决于其内在的 RNA 解旋酶活性以及与保守的核长非编码 RNA (lncRNA) Rmrp 的结合，Rmrp 在软骨毛发发育不全 (CHH) 患者中发生突变。小鼠中的一种靶向 Rmrp 突变（与 CHH 患者中的突变相对应）消除了 lncRNA 的染色质募集、增强 DDX5-RORγt 相互作用和 RORγt 靶基因转录的能力。 Rmrp 和 DDX5-RORγt 复合物之间联系的阐明揭示了 RNA 解旋酶和 lncRNA 在组织特异性转录调控中的作用，并为 Th17 依赖性疾病的治疗干预带来了新的机会。
Th17 lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. We identified the DEAD-box RNA helicase DDX5 as a RORγt partner that coordinates transcription of selective Th17 genes and is required for Th17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt and co-activate its targets depends on its intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in Cartilage-Hair Hypoplasia (CHH) patients. A targeted Rmrp mutation in mice, corresponding to one in CHH patients, abrogated the lncRNA’s chromatin recruitment, ability to potentiate DDX5-RORγt interaction and RORγt target gene transcription. Elucidation of the link between Rmrp and the DDX5-RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation and promises new opportunities for therapeutic intervention in Th17-dependent diseases.