Abstract
The m7G cap is ubiquitous on RNAPII-transcribed RNA and has fundamental roles in eukaryotic gene expression, however its in vivo role in mammals has remained unknown. Here, we identified the m7G cap methyltransferase, RNMT, as a key mediator of T cell activation, which specifically regulates ribosome production. During T cell activation, induction of mRNA expression and ribosome biogenesis drives metabolic reprogramming, rapid proliferation and differentiation generating effector populations. We report that RNMT is induced by T cell receptor (TCR) stimulation and co-ordinates the mRNA, snoRNA and rRNA production required for ribosome biogenesis. Using transcriptomic and proteomic analyses, we demonstrate that RNMT selectively regulates the expression of terminal polypyrimidine tract (TOP) mRNAs, targets of the m7G-cap binding protein LARP1. The expression of LARP1 targets and snoRNAs involved in ribosome biogenesis is selectively compromised in Rnmt cKO CD4 T cells resulting in decreased ribosome synthesis, reduced translation rates and proliferation failure. By enhancing ribosome abundance, upregulation of RNMT co-ordinates mRNA capping and processing with increased translational capacity during T cell activation.
Highlights
T cells have major roles in adaptive immunity; cytotoxic CD8 T cells directly kill infected or cancerous cells by the transfer of proteolytic enzymes and CD4 helper T cells coordinate the actions of other immune cells by the secretion of cytokines and factors
We report that RNMT is induced by T cell receptor (TCR) stimulation and co-ordinates the mRNA, snoRNA and rRNA production required for ribosome biogenesis
Consistent with this, we found that the m7G cap methyltransferase, RNMT, and co-factor, RAM, were upregulated downstream of T cell receptor (TCR) signalling, induced using crosslinking antibody stimulation, and maintained throughout CD4 and CD8 T cell activation in the presence of the stimulatory cytokine interleukin 2 (IL2) (Figure 1B, C, Supplementary Figure S1A–E)
Summary
T cells have major roles in adaptive immunity; cytotoxic CD8 T cells directly kill infected or cancerous cells by the transfer of proteolytic enzymes and CD4 helper T cells coordinate the actions of other immune cells by the secretion of cytokines and factors. Strong TCR signalling drives T cell activation, inducing cell growth, proliferation and differentiation into effector T cells. This requires the reprogramming of cellular metabolism [1,2] and reshaping of the proteome [3,4], which are co-ordinated by global and gene-specific increases in transcription and translation [5,6,7]. M7G cap formation involves cap guanosine addition to the 5 end of nascent RNA, catalysed by the capping enzyme RNGTT (RNA guanylyltransferase and 5 phosphatase), followed by cap guanosine N-7 methylation catalysed by RNMT (RNA guanine-7 methyltransferase) [12]. Most non-coding RNAs lose their m7G cap during maturation by cleavage or further modification to m2,2,7G trimethylguanosine
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