Aminoacyl tRNA synthetases and their connections to disease - PubMed (original) (raw)

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Aminoacyl tRNA synthetases and their connections to disease

Sang Gyu Park et al. Proc Natl Acad Sci U S A. 2008.

Abstract

Aminoacylation of transfer RNAs establishes the rules of the genetic code. The reactions are catalyzed by an ancient group of 20 enzymes (one for each amino acid) known as aminoacyl tRNA synthetases (AARSs). Surprisingly, the etiology of specific diseases-including cancer, neuronal pathologies, autoimmune disorders, and disrupted metabolic conditions-is connected to specific aminoacyl tRNA synthetases. These connections include heritable mutations in the genes for tRNA synthetases that are causally linked to disease, with both dominant and recessive disease-causing mutations being annotated. Because some disease-causing mutations do not affect aminoacylation activity or apparent enzyme stability, the mutations are believed to affect functions that are distinct from aminoacylation. Examples include enzymes that are secreted as procytokines that, after activation, operate in pathways connected to the immune system or angiogenesis. In addition, within cells, synthetases form multiprotein complexes with each other or with other regulatory factors and in that way control diverse signaling pathways. Although much has been uncovered in recent years, many novel functions, disease connections, and interpathway connections of tRNA synthetases have yet to be worked out.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Signaling network mediated by mammalian AARSs. Nine different AARSs (EP: glutamyl-prolyl-, I: isoleucyl-, L: leucyl-, M: methionyl-, Q: glutaminyl-, R: arginyl-, K: lysyl-, and D: aspartyl-tRNA synthetase) form a macromolecular complex with three nonenzymatic factors, AIMP1/p43, AIMP2/p38 and AIMP3/p18 (10). Among the components of the complex, EPRS is activated by IFN-γ and dissociates from the complex to form a new complex named GAIT (IFN-gamma-activated inhibitor of translation) that binds to the 3′UTR of the ceruloplasmin transcript for translational silencing (5). KRS is secreted to induce the inflammatory process (18), and QRS binds to apoptosis signal-regulating kinase 1 (ASK1) to regulate apoptosis in a glutamine-dependent manner (89). MRS is translocated to nucleoli to stimulate rRNA synthesis on growth stimuli (90). Among the nonenzyme factors, AIMP2 is translocated to the nucleus to suppress c-Myc via ubiquitin-dependent degradation of far upstream element binding protein (FBP) (64), whereas AIMP3 is mobilized by DNA damage (66) or an oncogenic stimulus (67) to activate p53 via ATM/ATR. AIMP1 is secreted as an extracellular multifunctional ligand active in inflammation (–93), angiogenesis (61, 62), wound healing (94, 95), and glucose metabolism (83), and it influences the autoimmune response via its association with gp96 (78). AIMP1 also down-regulates the signal mediated by TGF-β through the stabilization of SMAD specific E3 ubiquitin protein ligase 2 (Smurf2) (96). KRS-generated Ap4A releases microphthalmia-associated transcription factor (MITF) and upstream stimulatory factor (USF2) from their bound complexes for transcriptional control of target genes (97). KRS is packaged into the HIV virion via its interaction with the gag protein (98). Among noncomplex forming AARSs, WRS (tryptophanyl-tRNA synthetase) is secreted and its N-terminal truncation results in the formation of an active angiostatic cytokine that works via VE-cadherin (, , , –102). The active fragment of WRS also inhibits the response of endothelial cells to shear stress (100). YRS (tyrosyl-tRNA synthetase) is also secreted and cleaved into two distinct cytokines that work in angiogenesis as well as in the immune response (14, 15, 25, 103).

Fig. 2.

Linkage map of AARSs with various human diseases. Mutants of G/Y/ARS, mitochondrial DRS and AIMP2 are implicated in CMT, leukoencephalopathy and Parkinson's disease, respectively. The M, C, I, EP, F and KRSs are overexpressed in various human cancers, although the potential cause for the overexpression is probably idiosyncratic. AIMP3/p18 is a haploinsufficient tumor suppressor acting on ATM/ATR, thereby leading to activation of p53. The H, T, A, I, F, G, S and NRSs are implicated in the autoimmune diseases collectively designated “antisynthetase syndrome.” AIMP1 controls a lupus-like autoimmune disease via its interaction with gp96. The C-terminal domains of YRS and KRS work as inflammatory cytokines. The secretion of the N-terminal domain of YRS, N-terminal truncated WRS, and full-length AIMP1/p43 regulate angiogenesis. EPRS represses angiogenesis via translational silencing of VEGF-A (60). A mutation of mitochondrial LRS is associated with type 2 diabetes, even though the mutation does not affect its catalytic activity. Reduced activity of mitochondrial DRS is associated with leukoencephalopathy and lactate elevation. Mutations in mitochondrial tRNALys (104, 105), tRNALeu (106), and tRNASer (107) were shown to be associated with diabetes. AIMP1 works as hormone for glucose homeostasis.

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Aminoacyl tRNA synthetases and their connections to disease - PubMed (original) (raw)