Abstract
The global rise in type 2 diabetes results from a combination of genetic predisposition with environmental assaults that negatively affect insulin action in peripheral tissues and impair pancreatic β-cell function and survival. Nongenetic heritability of metabolic traits may be an important contributor to the diabetes epidemic. Transfer RNAs (tRNAs) are noncoding RNA molecules that play a crucial role in protein synthesis. tRNAs also have noncanonical functions through which they control a variety of biological processes. Genetic and environmental effects on tRNAs have emerged as novel contributors to the pathogenesis of diabetes. Indeed, altered tRNA aminoacylation, modification, and fragmentation are associated with β-cell failure, obesity, and insulin resistance. Moreover, diet-induced tRNA fragments have been linked with intergenerational inheritance of metabolic traits. Here, we provide a comprehensive review of how perturbations in tRNA biology play a role in the pathogenesis of monogenic and type 2 diabetes.
Highlights
Biology in the Pathogenesis ofType 2 diabetes (T2D) is a complex metabolic disease that accounts for more than80% of all diabetes cases
Charging, and Transfer RNAs (tRNAs) fragmentation adds complexity to this novel pathogenic mechanism contributing to impaired glucose metabolism
Further studies are needed to assess whether this is the result of palmitate-induced oxidative stress, and whether the impaired tRNALys modification contributes to palmitate-induced human β-cell demise
Summary
Type 2 diabetes (T2D) is a complex metabolic disease that accounts for more than. 80% of all diabetes cases. Modifications in the D or T loops are required for tRNA stability and functional folding [26] Due to their sequence differences, isoacceptors and isodecoders are unevenly modified resulting in tRNAs that carry the same aminoacid but have different physical and functional properties, providing unique characteristics to the cellular tRNA pool. A large variety of tRNA fragments exists which have been classified into seven groups based on their position within the parental tRNA sequence: 50 or 30 small tRNA fragments (tRFs) of ≤30 nucleotides that are generated from the 50 or 30 ends of the parental mature tRNA, internal tRNA fragments (i-tRFs) of varying lengths (16 to 33 nucleotides), 50 or 30 33 nucleotide-long tRNA halves (tRHs) and 50 U-tRFs and tRF-1s derived from precursor tRNAs and containing part of the 50 leader or 30 trailer sequence, respectively [35]. It was demonstrated that many tRFs contain 50 78 nucleotide-long “seed sequences” that, similar to miRNAs, match target mRNAs in their 30 UTR regions leading to RISC-mediated mRNA degradation [37,63,69,70]. tRNA fragments were shown to regulate protein translation through a variety of mechanisms, e.g., by sequestering mRNAs and preventing translation [28], interacting with the a subunit of eukaryotic translation initiation factor 2 (eIF2a) in the actively translating ribosome [49], preventing the eIF4G/eIF4A complex from stabilizing capped mRNAs which blocks translation initiation [29], interacting with active polysomes [33], disrupting the stability of the mammalian multisynthetase complex which coordinates the assembly of the mature ribosome, directly inhibiting ribosomal function [38,40], or by competing with the mRNA for ribosome binding [41]
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