EPRS1

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a multifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. Alternative splicing has been observed for this gene, but the full-length nature and biological validity of the variant have not been determined.

Glutamyl-Prolyl-tRNA Synthetase 1

EARS; EPRS; PARS; QARS; QPRS; HLD15; PIG32; GLUPRORS

Multifunctional protein which primarily functions within the aminoacyl-tRNA synthetase multienzyme complex, also known as multisynthetase complex. Within the complex it catalyzes the attachment of both L-glutamate and L-proline to their cognate tRNAs in a two-step reaction where the amino acid is first activated by ATP to form a covalent intermediate with AMP. Subsequently, the activated amino acid is transferred to the acceptor end of the cognate tRNA to form L-glutamyl-tRNA(Glu) and L-prolyl-tRNA(Pro).
Upon interferon-gamma stimulation, EPRS1 undergoes phosphorylation, causing its dissociation from the aminoacyl-tRNA synthetase multienzyme complex. It is recruited to form the GAIT complex, which binds to stem loop-containing GAIT elements found in the 3'-UTR of various inflammatory mRNAs, such as ceruloplasmin. The GAIT complex inhibits the translation of these mRNAs, allowing interferon-gamma to redirect the function of EPRS1 from protein synthesis to translation inhibition in specific cell contexts.
Furthermore, it can function as a downstream effector in the mTORC1 signaling pathway, by promoting the translocation of SLC27A1 from the cytoplasm to the plasma membrane where it mediates the uptake of long-chain fatty acid by adipocytes. Thereby, EPRS1 also plays a role in fat metabolism and more indirectly influences lifespan

Cellular response to insulin stimulus
Cellular response to type II interferon
Glutamyl-tRNA aminoacylation
Negative regulation of translation
Prolyl-tRNA aminoacylation
Regulation of long-chain fatty acid import into cell
tRNA aminoacylation for protein translation

Cytoplasm, cytosol
Membrane; Peripheral membrane
Note: Translocates from cytosol to membranes upon phosphorylation at Ser-999.

Leukodystrophy, hypomyelinating, 15 (HLD15):
An autosomal recessive disorder characterized by hypomyelinating leukodystrophy with thinning of the corpus callosum. Clinical features include motor and cognitive impairment appearing in the first or second decade of life, dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss.

Phosphorylated at Ser-886 by CDK5.
Phosphorylated at Ser-999 by RPS6KB1; triggers EPRS1 release from the aminoacyl-tRNA synthetase multienzyme complex.
In monocytes, the IFN-gamma-induced sequential phosphorylation at Ser-886 and Ser-999 releases EPRS1 from the aminoacyl-tRNA synthetase multienzyme complex, allowing its association with the GAIT complex. Phosphorylation at Ser-999 is specifically required for the RPL13A-mediated interaction of the GAIT complex with eIF4G.
Phosphorylation at Ser-999 by RPS6KB1, is also induced by insulin through activation of the mTORC1 signaling pathway and promotes the interaction of EPRS1 with SLC27A1.