The tRNA epitranscriptome may play a regulatory role in immunity and haematopoiesis
We know that the expression of the proteins that make up our bodies is very tightly regulated at many levels. In particular, the abundance of our various proteins is regulated via the transcription of the genes coding for their messenger RNA (mRNA) and then via the regulation of the half-life of the proteins formed. The expression of many proteins is also regulated in a more subtle, but no less biologically important way, by controlling the translation of mRNAs via various molecular mechanisms known as "translational" regulation. It has in this regard recently been shown that many mRNAs are the target of chemical modifications catalysed by dedicated enzymes, which consequently regulate their translation. An abundant literature is beginning to describe the role of what is currently called the mRNA epitranscriptome (i.e. mRNA modifications) in normal and pathological biological processes.
H
owever, mRNAs are not the most modified RNAs in our cells. The "award" of the modifications undoubtedly goes to another family of RNAs essential for protein production: transfer RNAs (tRNAs). TRNAs allow the translation of proteins by "pairing" the codons of mRNAs with their corresponding amino acid within the ribosomes. TRNAs can be subjected to almost a hundred distinct modifications, catalysed by a machinery involving hundreds of proteins. The biological role of this vast "tRNA epitranscriptome" is only just beginning to be studied in mammals, but it is already clear that the tRNA epitranscriptome is very important in central biological processes such as embryogenesis, brain development or even cancer, as shown by various publications notably by Pr Chariot and Dr Close, Dr Malgrange and Dr Nguyen of GIGA.
Two new publications by GIGA researchers now contribute to extending the scope of action of the tRNA epitranscriptome to the fields of immunity and haematopoiesis. To highlight this role, the authors turned to transgenic mouse models harbouring a loss, selectively in certain cells, of an enzyme that specifically modifies many tRNAs called Elp3 (Elongator subunit 3). In a first publication, the authors show that the loss of Elp3 in T lymphocytes, central actors of adaptive immunity, selectively represses the differentiation of T lymphocytes into so-called follicular helper T lymphocytes (TFH). Since these TFH lymphocytes are important in assisting antibody responses, transgenic mice showed reduced responses to vaccination, but were still able to eliminate the influenza virus or develop allergies.
In the second publication, the authors invalidated Elp3 in mouse haematopoietic stem cells (HSC). HSCs are responsible for the production of our blood cells and a large part of our immune cells throughout our lives. The loss of Elp3 leads a majority of HSC daughter cells to commit suicide when they need to differentiate, preventing them from giving birth to mature blood and immune cells. Thus, mice deficient in Elp3 in their HSCs develop severe anaemia reminiscent of certain human blood diseases. The reason for the suicide of the transgenic cells in the process of differentiation seems to be linked to the perception of a threat of cancerisation. Indeed, the suicide of cells not expressing Elp3 is entirely controlled by the tumour suppressor p53. Moreover, mice deficient for Elp3 in their HSCs spontaneously develop lymphomas/leukemias having mutated p53. In support of the transferability of these findings to human haematopoiesis, mutations affecting another enzyme acting in the same signalling pathway as Elp3 have very recently been identified as a probable cause of clonal haematopoiesis in humans, a pre-leukemic process.
Whether in T lymphocytes or HSCs, it seems that the loss of the changes catalysed by Elp3 is perceived by cells as a major metabolic problem, leading to the activation of a central regulator of metabolic stress called Activating Transcription Factor-4 through non-canonical mechanisms. These results thus suggest that while the tRNA epitranscriptome plays a direct role in mRNA translation, it is also integrated into cellular signalling pathways, and thereby plays important regulatory roles in immunity and haematopoiesis.
References
(1) Loss of the Transfer RNA Wobble Uridine-Modifying Enzyme Elp3 Delays T Cell Cycle Entry and Impairs T Follicular Helper Cell Responses through Deregulation of Atf4, Lemaitre P, Bai Q, Legrand C, Chariot A, Close P, Bureau F, Desmet CJ, J Immunol, 2021, 206, doi: 10.4049/jimmunol.2000521
(2) Loss of tRNA-modifying enzyme Elp3 activates a p53-dependent antitumor checkpoint in hematopoiesis, Rosu A, El Hachem N, Rapino F, Rouault-Pierre K, Jorssen J, Somja J, Ramery E, Thiry M, Nguyen L, Jacquemyn M, Daelemans D, Adams CM, Bonnet D, Chariot A, Close P, Bureau F, Desmet CJ, J Exp Med, 2021, 218:3, e20200662
