Impaired miRNA degradation by post-transcriptional addition of 3’ cytosine and adenine in T cell activation

Abstract

MiRNA repertoire of T cells undergoes extensive changes in response to activation. Whereas global miRNA downregulation occurs few hours after activation, some individual miRNAs are specifically up- or down-regulated. In this study, we have assessed miRNA expression and post-transcriptional modification kinetics in human primary CD4+ T cells upon short-term stimulation with anti-CD3/antiCD28 or IFN I using Next Generation Sequencing. Multiple miRNAs not related before with T cell activation profile have been identified as differentially expressed. Downregulated miRNAs presented higher 3' uridylation. Dis3L2 and Eri1 (3' to 5' exoribonucleases that prefer uridylated RNA as substrates) increased their expression upon TCR stimulation, probably generating an adverse environment for miRNAs. Remarkably, non-templated cytosine additions to 3' end, previously unknown to be a relevant post-transcriptional modification mechanism, were overrepresented in upregulated miRNAs, together with high levels of adenylation. In the midst of an increasing presence of exoribonucleases, miRNAs multiplying their levels may successfully escape degradation due to 3' cytosine and adenine addition. These protective signals open a new avenue to improve miRNA stability for therapy in T cells.

Post‐transcriptional control of T‐cell cytokine production: Implications for cancer therapy

“…An overview of the regulatory elements present in the three key cytokines produced by T cells in the context of anti‐tumour effector function (IFN‐γ, TNF‐α and IL‐2) and the regulators thereof can be found in Table 1. While miRNA transcript binding and mRNA modifications can significantly alter lymphocyte (cytokine) protein production [54,109,110], here, only post‐transcriptional regulation through (repetitive) sequence elements and the role RBPs play therein are discussed (summarized in Figure 3), as these processes have recently been explored as potential therapeutic targets through genome editing with, for example, CRISPR/Cas9 [42,111].…”