Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease

Abstract

Transfer RNAs (tRNAs) are key players of protein synthesis, as they decode the genetic information organized in mRNA codons, translating them into the code of 20 amino acids. To be fully active, tRNAs undergo extensive post-transcriptional modifications, catalyzed by different tRNA-modifying enzymes. Lack of these modifications increases the level of missense errors and affects codon decoding rate, contributing to protein aggregation with deleterious consequences to the cell. Recent works show that tRNA hypomodification and tRNA-modifying-enzyme deregulation occur in several diseases where proteostasis is affected, namely, neurodegenerative and metabolic diseases. In this review, we discuss the recent findings that correlate aberrant tRNA modification with proteostasis imbalances, in particular in neurological and metabolic disorders, and highlight the association between tRNAs, their modifying enzymes, translational decoding, and disease onset.

Keywords: conformational disorders; protein aggregation; proteostasis; tRNA modifications; tRNA-modifying enzymes; transfer RNA; translation.

Figure 1

Schematic representation of the tRNA secondary structure with respective tRNA-modifying enzymes and modifications (in parenthesis). Connecting lines between RNA residues indicate base pairing. Abbreviations: tRNA, transfer RNA; m¹G, 1-methylguanosine; m²₂G, N2,N2-dimethyl guanosine; Cm, 2′-O-methylcytidine; m³C, 3-methylcytidine Gm, 2′-O-methylguanosine; ncm⁵Um, 5-carbamoylmethyl-2′-O-methyluridine; m⁵C, 5-methylcytosine; ncm⁵mU, 5-methoxycarbonylmethyluridine; mcm⁵s²U, 5-methoxycarbonylmethyl-2-thiouridine; Q, queuosine; s²U, 2-thiouridine τm⁵U, 5-taurinomethyluridine; τm⁵s²U, 5-taurinomethyl-2-thiouridine; I⁶A, N6-isopentenyladenosine; ms²t⁶A, 2-methylthio-N6-threonyl carbamoyladenosine; Ψ, pseudouridine; m¹A, 1-methyladenosine.

Figure 2

Yeast biosynthesis pathways of modified wobble uridines in different tRNA substrates catalyzed by the Elongator complex (Elp1–Elp6), Trm9, and Urm1 enzymes and the ubiquitin-ligase-like proteins, namely, Uba4, Ncs2, and Ncs6. In yeast, the Elongator complex (Elp1–Elp6) catalyze the wobble uridine (U₃₄) modifications that form 5-carbamoylmethyluridine (ncm⁵U₃₄) and 5-carboxymethyluridine (cm⁵U₃₄). Then, the methyltransferase Trm9 uses cm⁵U₃₄ as a substrate in different tRNAs: tRNA ^Lys(UUU) tRNA ^Gln(UUG), tRNA ^Gly(UCC), tRNA ^Arg(UCU), and tRNA ^Glu(UUC). Subsequent addition of a 2-thiol group by an enzyme cascade involving Urm1 and Uba4, Ncs2, and Ncs6 occurs in three of these tRNAs: (tRNA^Lys(UUU), tRNA^Gln(UUG), and tRNA^Glu(UUC)). All modified nucleosides presented in this figure can be found in the MODOMICS database. Red dashed boxes represent the modification catalyzed by the respective enzymes in each step. Abbreviations: tRNA, transfer RNA; ncm⁵U, 5-carbamoylmethyluridine; cm⁵U, 5-carboxymethyluridine; mcm⁵U, 5-methoxycarbonylmethyluridine; mcm⁵s²U, 5-methoxycarbonylmethyl-2-thiouridine.

Figure 3

Identification of tRNA-modifying enzymes and respective tRNA modification sites involved in neurological and metabolic disorders. Schematic representation of the clover leaf tRNA secondary structure including tRNA-modifying enzymes (in bold), modifications (in parenthesis), and human diseases associated with cytosolic and mitochondrial tRNA defects marked in blue and orange, respectively. Abbreviations: tRNA, transfer RNA; m¹G, 1-methylguanosine; m²₂G, N2,N2-dimethyl guanosine; Cm, 2′-O-methylcytidine; Gm, 2′-O-methylguanosine; ncm⁵Um, 5-carbamoylmethyl-2′-O-methyluridine; m⁵C, 5-methylcytosine; ncm⁵mU, 5-methoxycarbonylmethyluridine; mcm⁵s²U, 5-methoxycarbonylmethyl-2-thiouridine, τm⁵U, 5-taurinomethyluridine; τm⁵s²U, 5-taurinomethyl-2-thiouridine; I⁶A, N6-isopentenyladenosine; ms²t⁶A, 2-methylthio-N6-threonyl carbamoyladenosine; Ψ, pseudouridine; m¹A, 1-methyladenosine; ALS, amyotrophic lateral sclerosis; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERFF, myoclonus epilepsy associated with ragged red fibers.