Extra-translational role of aminoacyl-tRNA synthetases in connection to disease Abstract: My goal is to understand the expanded functions of glycyl-tRNA synthetase (GlyRS) and how they connect with Charcot-Marie-Tooth (CMT) diseases. GlyRS is one of 20 members of the aminoacyl-tRNA synthetase (AARS) family that catalyzes aminoacylation of transfer tRNAin the first step of protein synthesis. Dominant mutations of GARS (gene for GlyRS) and YARS (gene for tyrosyl-tRNA synthetase) have been identified in the human population to cause Charcot-Marie-Tooth (CMT) diseases. Also known as hereditary motor and sensory neuropathies, CMT diseases are the most common heritable peripheral neuropathy, occurring with a frequency of approximately 1 in 2500 individuals. The CMT phenotype does not arise from a reduction in the essential aminoacylation function. This observation led to our hypothesis that these two tRNA synthetases have expanded functions (beyond aminoacylation) that are critical to understanding their connection to CMT. The focus of the proposal is on GlyRS. A search for interaction partners of GlyRS identified Daxx, a protein that interacts with the cytoplasmic domain of Fas. Fas is a member of the tumor necrosis factor receptor superfamily, and the Fas-Daxx interaction enhances Fas-mediated apoptosis. Significantly, The Fas-Daxx pathway is implicated in CMT, as well as in many other neurological disorders including Amyotrophic Lateral Sclerosis and Parkinson's disease. These considerations raised the possibility that the interaction between GlyRS and Daxx is relevant to the CMT disease-causing mechanism. Surprisingly, we found that a modified form of GlyRS specifically interacts with Daxx. We have identified the modifier of GlyRS to be a ubiquitin-like protein called NEDD8. NEDDylation is known to regulate the function of its substrates. Interestingly, the residue on NEDD8 for conjugation to substrate is the C-terminal glycine, which is conserved in ubiquitin and in almost all ubiquitin-like proteins. The first reaction in NEDDylation is the adenylation of the C- terminal glycine by condensation with ATP. It is chemically the same reaction as the first step of catalysis by GlyRS in aminoacylation. This consideration led us to propose that GlyRS is involved in the NEDDylation of Daxx which, in turn, regulates Daxx-mediated apoptosis. Indeed, we found that GlyRS-associated Daxx is NEDDylated. Thus, the work proposed here will advance understanding of the extra-translational roles of AARS and their possible connection to human disease.
Narrative This project will aid in understanding how tRNA synthetases function in connection to Charcot-Marie-Tooth disease, which is the most common hereditary neuropathy. The knowledge we gain in this study will also shed light on other neurological diseases such as Amyotrophic Lateral Sclerosis (Lou Gehrig's disease) and Parkinson's disease.
|Mo, Zhongying; Zhao, Xiaobei; Liu, Huaqing et al. (2018) Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy. Nat Commun 9:1007|
|Xu, Xiaoling; Zhou, Huihao; Zhou, Quansheng et al. (2018) An alternative conformation of human TrpRS suggests a role of zinc in activating non-enzymatic function. RNA Biol 15:649-658|
|Xu, Zhiwen; Lo, Wing-Sze; Beck, David B et al. (2018) Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function. Am J Hum Genet 103:100-114|
|Sleigh, James N; Dawes, John M; West, Steven J et al. (2017) Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations. Proc Natl Acad Sci U S A 114:E3324-E3333|
|Sleigh, James N; Gómez-Martín, Adriana; Wei, Na et al. (2017) Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis. Sci Rep 7:9216|
|Mo, Zhongying; Zhang, Qian; Liu, Ze et al. (2016) Neddylation requires glycyl-tRNA synthetase to protect activated E2. Nat Struct Mol Biol 23:730-7|
|Niehues, Sven; Bussmann, Julia; Steffes, Georg et al. (2015) Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases. Nat Commun 6:7520|
|Amin, Neal D; Bai, Ge; Klug, Jason R et al. (2015) Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure. Science 350:1525-9|
|He, Weiwei; Bai, Ge; Zhou, Huihao et al. (2015) CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature 526:710-4|
|Zhou, Jie J; Wang, Feng; Xu, Zhiwen et al. (2014) Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis. J Biol Chem 289:19269-75|
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