Non-canonical roles of lysyl-tRNA synthetase in health and disease

Motzik, Alex; Nechushtan, Hovav; Foo, Shen Yun; Razin, Ehud

doi:10.1016/j.molmed.2013.07.011

Cited by 35 publications

(30 citation statements)

References 52 publications

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“…KARS is also part of the multi-synthetase complex (MSC) and can exist as either a dimer or tetramer. KARS has additional non-canonical functions involved in signaling, cell migration, and viral HIV infection, some of which are activated by post-translational modification (Motzik et al, 2013). Mitogen-activated kinase (MAPK) phosphorylation induces release of one dimer from the MSC for translocation into the nuclease, while the other dimer remains with the MSC to continue protein synthesis (Ofir-Birin et al, 2013).…”

Section: Aminoacyl-trna Synthetases and Diseasementioning

confidence: 99%

Transfer RNA and human disease

2014

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Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are “hotspots” for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

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Section: Aminoacyl-trna Synthetases and Diseasementioning

confidence: 99%

Transfer RNA and human disease

2014

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“…Recognized as a conserved cellular enzyme, lysyl-tRNA synthetase (LysRS) takes part in protein synthesis and circulates in multiple compartments (the nucleus, mitochondria, and plasma membrane) for transcriptional regulation, cytokine-like signaling, and the transport of proteins to the cell membrane (366). Although a direct interaction between capsid and Vpr has not been reported to our knowledge, LysRS physically interacts with both HIV-1 Vpr (159) and capsid Gag (367)(368)(369).…”

Section: Gag -Lysrs-vpr Associationmentioning

confidence: 99%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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“…Along with these three ARS genes, lysyl-tRNA synthetase, KARS, mutation is also identified in CMT intermediate recessive type B [87]. P.L133H and p.Y173SfsX7 mutations sternly influence the KARS activity in CMT [90]. The last few years witnessed a number of ARS mutations as being the cause of CMT.…”

Section: Ars/ars2 Gene Mutation Causing Diseasesmentioning

confidence: 99%