Nitrosative stress inhibits aminoacylation and editing activities of mitochondrial threonyl-tRNA synthetase by S-nitrosation
Open Access
- 2 June 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 48 (12), 6799-6810
- https://doi.org/10.1093/nar/gkaa471
Abstract
Structure and/or function of proteins are frequently affected by oxidative/nitrosative stress via posttranslational modifications. Aminoacyl-tRNA synthetases (aaRSs) constitute a class of ubiquitously expressed enzymes that control cellular protein homeostasis. Here, we found the activity of human mitochondrial (mt) threonyl-tRNA synthetase (hmtThrRS) is resistant to oxidative stress (H2O2) but profoundly sensitive to nitrosative stress (S-nitrosoglutathione, GSNO). Further study showed four Cys residues in hmtThrRS were modified by S-nitrosation upon GSNO treatment, and one residue was one of synthetic active sites. We analyzed the effect of modification at individual Cys residue on aminoacylation and editing activities of hmtThrRS in vitro and found that both activities were decreased. We further confirmed that S-nitrosation of mtThrRS could be readily detected in vivo in both human cells and various mouse tissues, and we systematically identified dozens of S-nitrosation-modified sites in most aaRSs, thus establishing both mitochondrial and cytoplasmic aaRS species with S-nitrosation ex vivo and in vivo, respectively. Interestingly, a decrease in the S-nitrosation modification level of mtThrRS was observed in a Huntington disease mouse model. Overall, our results establish, for the first time, a comprehensive S-nitrosation-modified aaRS network and a previously unknown mechanism on the basis of the inhibitory effect of S-nitrosation on hmtThrRS.Funding Information
- National Key Research and Development Program of China (2017YFA0504000)
- Natural Science Foundation of China (31822015, 81870896, 31670801, 91940302, 31500644, 31570792, 91849203, 31570857)
- Chinese Academy of Sciences (XDB19010203, XDB39000000)
- Shanghai Key Laboratory of Embryo Original Diseases (Shelab201904)
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