Dynamic changes in tRNA modifications and abundance during T cell activation

Abstract

The tRNA pool determines the efficiency, throughput, and accuracy of translation. Previous studies have identified dynamic changes in the tRNA (transfer RNA) supply and mRNA (messenger RNA) demand during cancerous proliferation. Yet dynamic changes may also occur during physiologically normal proliferation, and these are less well characterized. We examined the tRNA and mRNA pools of T cells during their vigorous proliferation and differentiation upon triggering their antigen receptor. We observed a global signature of switch in demand for codons at the early proliferation phase of the response, accompanied by corresponding changes in tRNA expression levels. In the later phase, upon differentiation, the response of the tRNA pool relaxed back to the basal level, potentially restraining excessive proliferation. Sequencing of tRNAs allowed us to evaluate their diverse base-modifications. We found that two types of tRNA modifications, wybutosine and ms2t6A, are reduced dramatically during T cell activation. These modifications occur in the anticodon loops of two tRNAs that decode “slippery codons,” which are prone to ribosomal frameshifting. Attenuation of these frameshift-protective modifications is expected to increase the potential for proteome-wide frameshifting during T cell proliferation. Indeed, human cell lines deleted of a wybutosine writer showed increased ribosomal frameshifting, as detected with an HIV gag-pol frameshifting site reporter. These results may explain HIV’s specific tropism toward proliferating T cells since it requires ribosomal frameshift exactly on the corresponding codon for infection. The changes in tRNA expression and modifications uncover a layer of translation regulation during T cell proliferation and expose a potential tradeoff between cellular growth and translation fidelity.

Essentiality and dynamic expression of the human tRNA pool during viral infection

“…We further examined and quantified the change in tRNA modifications during HCMV infection based on tRNA sequencing and the effects of modifications on the obtained sequence, as described by Rak et al, 2021. We found that the level of most of the modifications does not change between uninfected and late-infected samples (Figure 2A, r=0.95, p<0.001).…”

tModBase: deciphering the landscape of tRNA modifications and their dynamic changes from epitranscriptome data

“…using LC–MS/MS techniques ( Supplementary Table S3 ) ( 9–11 , 13–15 , 65 , 66 ). Recent studies using HTS techniques have identified specific tRNA modifications in human and mouse cells that are significantly altered under pathogenic infection ( 67 , 68 ) and during T cell activation ( 32 ). This evidence implies that dynamic changes in tRNA modifications may be a general response of cells to stress conditions; however, the modifications that can be detected by LC–MS/MS methods cannot clarify the specific tRNA isotypes, and the data obtained from HTS are currently far from sufficient.…”

tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets

“…The level of tRNA modification is altered during T-cell activation. It has been found that yW and ms 2 t 6 A modifications are significantly reduced during T cell proliferation, which may be to reduce the occurrence of ribosomal frameshifting and improve translational fidelity [79]. A recent study revealed that TRMT61A-mediated m 1 A modification of the tRNA 58 promotes the translation of multiple key proteins such as MYC by modulating codon decoding, to ensure a rapid immune response in CD4 + T cells (Figure 3B).…”