Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom.
Institute of Ecology & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom.
RNA. 2023 Dec 18;30(1):26-36. doi: 10.1261/rna.079030.121.
Increasing evidence suggests mammalian Argonaute (Ago) proteins partition into distinct complexes within cells, but there is still little biochemical or functional understanding of the miRNAs differentially associated with these complexes. In naïve T cells, Ago2 is found almost exclusively in low molecular weight (LMW) complexes which are associated with miRNAs but not their target mRNAs. Upon T-cell activation, a proportion of these Ago2 complexes move into a newly formed high molecular weight (HMW) RNA-induced silencing complex (RISC), which is characterized by the presence of the GW182 protein that mediates translational repression. Here, we demonstrate distinct partitioning of miRNAs and isomiRs in LMW versus HMW RISCs upon antigen-mediated activation of CD8 T cells. We identify miR-7 as highly enriched in HMW RISC and demonstrate that miR-7 inhibition leads to increased production of IL-2 and up-regulation of the IL-2 receptor, the transferrin receptor, CD71 and the amino acid transporter, CD98. Our data support a model where recruitment of miR-7 to HMW RISC restrains IL-2 signaling and the metabolic processes regulated by IL-2.
越来越多的证据表明哺乳动物 Argonaute（AGO）蛋白在细胞内分成不同的复合物，但对于与这些复合物差异相关的 miRNAs 的生物化学或功能仍知之甚少。在幼稚 T 细胞中，AGO2 几乎只存在于与 miRNAs 相关但不与它们的靶 mRNAs 相关的低分子量（LMW）复合物中。T 细胞激活后，这些 AGO2 复合物中的一部分会进入新形成的高分子量（HMW）RNA 诱导沉默复合物（RISC），其特征是存在介导翻译抑制的 GW182 蛋白。在这里，我们证明了在抗原介导的 CD8 T 细胞激活过程中，miRNAs 和 isomiRs 在 LMW 与 HMW RISCs 中的不同分配。我们确定 miR-7 在 HMW RISC 中高度富集，并证明 miR-7 抑制会导致 IL-2 的产生增加和 IL-2 受体、转铁蛋白受体、CD71 和氨基酸转运体 CD98 的上调。我们的数据支持这样一种模型，即 miR-7 被招募到 HMW RISC 中会抑制 IL-2 信号和受 IL-2 调节的代谢过程。
