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tRNA in the pathogenesis of diabetes. Invited lecture.

par Igoillo Esteve, Mariana
Référence Annual Meeting of the European Association for the Study of Diabetes (EASD) (September 2022: Stockolm, Sweden)
Publication Non publié, 2022-09-22

Communication à un colloque

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Résumé :

This presentation focuses on the link between altered transfer RNA (tRNA) modifications and tRNA fragmentation and diabetes. tRNAs are RNA molecules carrying aminoacids to the ribosome during protein synthesis. Once synthesized, the tRNAs acquire many posttranscriptional modifications that control their folding, stability, and function. These modifications are introduced by very specific tRNA modifying enzymes that, when mutated, may cause human disease including diabetes. In this lecture Prof. Igoillo-Esteve highlights their initial discovery showing that inactivating mutations in the TRMT10A gene, encoding a tRNA methyltransferase, cause young onset diabetes and microcephaly. This initial finding was thereafter reinforced by 9 additional independent publications associating various TRMT10A inactivating mutations with a similar syndrome of diabetes and microcephaly.She shows that the absence of TRMT10A sensitizes pancreatic β-cells to apoptosis and induces gene and protein expression changes in these cells. She also demonstrates that, at molecular level, the lack of TRMT10A results in reduced methylation of several tRNAs, some of which are prone to enzymatic cleavage leading to the production of various tRNA-derived fragments in pancreatic β-cells. The tRNA fragments are a new class of small non-coding RNAs that can modulate different cellular processes including gene and protein expression, cell division and apoptosis. Prof. Igoillo-Esteve shows that, under TRMT10A deficiency, the accumulation of tRNA fragments derived from the 5’ end of the tRNA that transports glutamine (5’-tRFGln) induces β-cell apoptosis and is one of the mediators of β-cell demise caused by the lack in TRMT10A. She mentions that coxsackie virus infections (that are associated with the development of type 1 diabetes) reduce TRMT10A expression in pancreatic β-cells suggesting that tRNA fragmentation may also lead to β-cell dead in type 1 diabetes. By using targeted and high-throughput approaches in a wide variety of models of TRMT10A deficiency such as TRMT10A-silenced human β-cells and human pancreatic islets, and inducible pluripotent stem cells (iPSC) differentiated into β-cells from control and TRMT10A-deficient individuals, she is now studying the role of tRNA fragments in the modulation of gene and protein expression, and the molecular mechanisms involved. This will help to understand how the tRNA fragments identified contribute to the development of diabetes. In Conclusion, in this lecture Prof. Igoillo-Esteve provides evidence of a novel mechanism of pancreatic β-cell failure in diabetes, involving impaired tRNA methylation and tRNA fragmentation due to reduced expression of the tRNA-modifying enzyme TRMT10A. These findings highlight the importance of tRNAs and their modifications in the regulation of pancreatic β-cell fate.