under conditions of stress, several MSC components, including EPRS, methionyl-tRNA synthetase (MRS), lysyl-tRNA synthetase (KRS), AIMP1 and AIMP2, are released from the complex through post-translational modifications to exert activities during non-translational events such as inflammation, cell metabolism, angiogenesis, and tumorigenesis. Phosphorylation is the critical regulatory mechanism that determines the non-translational function of ARSs in cells, overview
the multi-tRNA synthetase complex (MSC) component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induces its dissociation from the MSC, after which it is guided to the antiviral signaling pathway, where it interacts with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. EPRS protects MAVS from PCBP2-mediated ubiquitination. The stimulus-inducible activation of MAVS by enzyme EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection. Phosphorylation of EPRS at Ser990 is the driving force that leads to the antiviral roles of EPRS in regulating MAVS
mechanism of translation control of enzyme EPRS involving increased translation initiation stringency during stress-induced eIF2alpha-P, facilitated ribosome bypass of upstream ORFs, allowing for increased translation of the EPRS coding region. The 5'-leader of the EPRS mRNA directs preferential translation. Although a portion of the ribosomes that translate uORF2 can reinitiate downstream, scanning ribosomes also bypass uORF2 because of its noncanonical UUG1 initiation codon and initiate translation at the downstream coding sequence. UUG1 and CUG2 are overall repressing elements in EPRS translation control. Model for EPRS translation control, overview
enzyme is part of a high molecular mass aminoacyl-tRNA synthetase complex, which has a coherent structure, that can be visualized by electron microscopy
infection-specific phosphorylation of EPRS at Ser990 induces its dissociation from the MSC, after which it is guided to the antiviral signaling pathway, where it interacts with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity
siRNA-mediated enzyme knockout in RAW-264.7 cells. Activation of the interferon-related signaling molecules IRF3 and STAT1 is significantly lower in cells in which EPRS is knocked down than in their EPRS-sufficient counterparts . RAW-264.7 cells stably overexpressing EPRS show significantly less viral replication and more production of IFN-beta and interleukin-6 following infection with PR8 or VSV than those of their counterparts with basal expression of EPRS
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant tagged wild-type and mutant enzymes from Escherichia coli strain Escherichia coli BL21-CodonPlus (DE3)-RIPL by affinity chromatography and gel filtration
the translation of the glutamyl-prolyl-tRNA synthetase gene EPRS is enhanced in response to phosphorylated eukaryotic initiation factor 2, eIF2alpha-P, mechanism of translation control involving increased translation initiation stringency during stress-induced eIF2alpha-P, facilitated ribosome bypass of upstream ORFs, allowing for increased translation of the EPRS coding region, overview. Both halofuginone and thapsigargin treatment result in a 2.5fold induction of EPRS expression
Translation regulation of the glutamyl-prolyl-tRNA synthetase gene EPRS through bypass of upstream open reading frames with noncanonical initiation codons
Lee, E.Y.; Lee, H.C.; Kim, H.K.; Jang, S.Y.; Park, S.J.; Kim, Y.H.; Kim, J.H.; Hwang, J.; Kim, J.H.; Kim, T.H.; Arif, A.; Kim, S.Y.; Choi, Y.K.; Lee, C.; Lee, C.H.; Jung, J.U.; Fox, P.L.; Kim, S.; Lee, J.S.; Kim, M.H.
Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity
Nat. Immunol.
17
1252-1262
2016
Homo sapiens (P07814), Mus musculus (Q8CGC7), Mus musculus C57BL/6 (Q8CGC7)