Aminoacyl‐tRNA synthetases in medicine and disease

Yao, Peng; Fox, Paul L.

doi:10.1002/emmm.201100626

Cited by 232 publications

(225 citation statements)

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“…37 We favor a shared pathogenic mechanism between AARS mutation and other tRNA synthetase mutations that cause peripheral neuropathy. The most insight into the mechanism of tRNA synthetase-linked neuropathy comes from the study of GARS-linked dominantly inherited CMT2D.…”

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confidence: 99%

A novel AARS mutation in a family with dominant myeloneuropathy

et al. 2015

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Objective: To determine the genetic cause of neurodegeneration in a family with myeloneuropathy. Methods:We studied 5 siblings in a family with a mild, dominantly inherited neuropathy by clinical examination and electrophysiology. One patient had a sural nerve biopsy. After ruling out common genetic causes of axonal Charcot-Marie-Tooth disease, we sequenced 3 tRNA synthetase genes associated with neuropathy.Results: All affected family members had a mild axonal neuropathy, and 3 of 4 had lower extremity hyperreflexia, evidence of a superimposed myelopathy. A nerve biopsy showed evidence of chronic axonal loss. All affected family members had a heterozygous missense mutation c.304G.C (p.Gly102Arg) in the alanyl-tRNA synthetase (AARS) gene; this allele was not identified in unaffected individuals or control samples. The equivalent change in the yeast ortholog failed to complement a strain of yeast lacking AARS function, suggesting that the mutation is damaging.Conclusion: A novel mutation in AARS causes a mild myeloneuropathy, a novel phenotype for patients with mutations in one of the tRNA synthetase genes. Charcot-Marie-Tooth disease (CMT) and hereditary motor and sensory neuropathy (HMSN) are alternative names for inherited neuropathies that are not part of more complex syndromes. With an estimated prevalence of 1 in 2,500 persons, CMT/HMSN is one of the commonest neurogenetic diseases and is subdivided according to clinical, electrophysiologic, histologic, and genetic features.1 CMT2/HMSN-II is a dominantly inherited axonal neuropathy, with nerve conduction velocities greater than 38 m/s. Mutations in more than 20 different genes cause autosomal dominant CMT2. With the exception of some MPZ mutations, these mutations are thought to produce a neuropathy through their direct effects in neurons. Mutations in genes that encode aminoacyl-tRNA synthetases (ARS) cause some forms of CMT2. These enzymes charge tRNAs with their cognate amino acids, establishing the genetic code. Mutations in the glycyl-tRNA synthetase (GARS) gene were the first to be described, found in patients with dominant purely motor (hereditary motor neuropathy 5A) or dominant motor predominant (CMT2D) neuropathy. ; and methionyl-tRNA synthetase (MARS) in late-onset, dominant

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confidence: 99%

A novel AARS mutation in a family with dominant myeloneuropathy

et al. 2015

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“…In mammals, nine tRNA synthetases, including LysRS, and three scaffolding proteins, aminoacyl-tRNA synthetase-interacting proteins (AIMPs), are part of a multi-aminoacyl-tRNA synthetase complex (MSC) (13). It has been shown that nearly all members of the tRNA synthetase family, whether or not they are components of the MSC, carry out alternative nontranslational functions in response to various intraand extracellular stimuli (14,15).…”

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confidence: 99%

HIV-1 Exploits a Dynamic Multi-aminoacyl-tRNA Synthetase Complex To Enhance Viral Replication

Duchon

Gelais

Titkemeier

et al. 2017

J Virol

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A hallmark of retroviruses such as human immunodeficiency virus type 1 (HIV-1) is reverse transcription of genomic RNA to DNA, a process that is primed by cellular tRNAs. HIV-1 recruits human tRNA Lys3 to serve as the reverse transcription primer via an interaction between lysyl-tRNA synthetase (LysRS) and the HIV-1 Gag polyprotein. LysRS is normally sequestered in a multi-aminoacyltRNA synthetase complex (MSC). Previous studies demonstrated that components of the MSC can be mobilized in response to certain cellular stimuli, but how LysRS is redirected from the MSC to viral particles for packaging is unknown. Here, we show that upon HIV-1 infection, a free pool of non-MSC-associated LysRS is observed and partially relocalized to the nucleus. Heat inactivation of HIV-1 blocks nuclear localization of LysRS, but treatment with a reverse transcriptase inhibitor does not, suggesting that the trigger for relocalization occurs prior to reverse transcription. A reduction in HIV-1 infection is observed upon treatment with an inhibitor to mitogen-activated protein kinase that prevents phosphorylation of LysRS on Ser207, release of LysRS from the MSC, and nuclear localization. A phosphomimetic mutant of LysRS (S207D) that lacked the capability to aminoacylate tRNA Lys3 localized to the nucleus, rescued HIV-1 infectivity, and was packaged into virions. In contrast, a phosphoablative mutant (S207A) remained cytosolic and maintained full aminoacylation activity but failed to rescue infectivity and was not packaged. These findings suggest that HIV-1 takes advantage of the dynamic nature of the MSC to redirect and coopt cellular translation factors to enhance viral replication.IMPORTANCE Human tRNA Lys3 , the primer for reverse transcription, and LysRS are essential host factors packaged into HIV-1 virions. Previous studies found that tRNA Lys3 packaging depends on interactions between LysRS and HIV-1 Gag; however, many details regarding the mechanism of tRNA Lys3 and LysRS packaging remain unknown. LysRS is normally sequestered in a high-molecular-weight multi-aminoacyl-tRNA synthetase complex (MSC), restricting the pool of free LysRS-tRNA Lys . Mounting evidence suggests that LysRS is released under a variety of stimuli to perform alternative functions within the cell. Here, we show that HIV-1 infection results in a free pool of LysRS that is relocalized to the nucleus of target cells. Blocking this pathway in HIV-1-producing cells resulted in less infectious progeny virions. Understanding the mechanism by which LysRS is recruited into the viral assembly pathway can be exploited for the development of specific and effective therapeutics targeting this nontranslational function.KEYWORDS lysyl-tRNA synthetase, human immunodeficiency virus, multisynthetase complex, nuclear localization, tRNA primer packaging

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“…The cytoplasmic aminoacyl tRNA synthetase genes are designated with single letter amino acid code followed by RS; the mitochondrial counterpart has a '2' suffix. In human, the number of ARS/ARS2 genes is 37, distinguished into two distinct sets based on protein localization; 18 cytoplasmic ARS (including the bifunctional glutamyl-prolyl-tRNA synthetase, EPRS, in charge for aminoacylation of Glu and Pro, FARS needs two separate genes A and B); 17 mitochondrial ARS2 (QARS2 does not exist) and 2 dual-localized ARSs, GARS and KARS, in both cytoplasm and mitochondria [6][7][8]. The mitochondrial translation machinery is a combination of products of nuclear and mtDNA-encoded genes.…”

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confidence: 99%