The GAIT translational control system

Abstract

The interferon (IFN)-γ-activated inhibitor of translation (GAIT) system directs transcript-selective translational control of functionally related genes. In myeloid cells, IFN-γ induces formation of a multiprotein GAIT complex that binds structural GAIT elements in the 3'-untranslated regions (UTRs) of multiple inflammation-related mRNAs, including ceruloplasmin and VEGF-A, and represses their translation. The human GAIT complex is a heterotetramer containing glutamyl-prolyl tRNA synthetase (EPRS), NS1-associated protein 1 (NSAP1), ribosomal protein L13a (L13a), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). A network of IFN-γ-stimulated kinases regulates recruitment and assembly of GAIT complex constituents. Activation of cyclin-dependent kinase 5 (Cdk5), mammalian target of rapamycin complex 1 (mTORC1), and S6K1 kinases induces EPRS release from its parental multiaminoacyl tRNA synthetase complex to join NSAP1 in a 'pre-GAIT' complex. Subsequently, the DAPK-ZIPK kinase axis phosphorylates L13a, inducing release from the 60S ribosomal subunit and binding to GAPDH. The subcomplexes join to form the functional GAIT complex. Each constituent has a distinct role in the GAIT system. EPRS binds the GAIT element in target mRNAs, NSAP1 negatively regulates mRNA binding, L13a binds eIF4G to block ribosome recruitment, and GAPDH shields L13a from proteasomal degradation. The GAIT system is susceptible to genetic and condition-specific regulation. An N-terminus EPRS truncate is a dominant-negative inhibitor ensuring a 'translational trickle' of target transcripts. Also, hypoxia and oxidatively modified lipoproteins regulate GAIT activity. Mouse models exhibiting absent or genetically modified GAIT complex constituents are beginning to elucidate the physiological role of the GAIT system, particularly in the resolution of chronic inflammation. Finally, GAIT-like systems in proto-chordates suggests an evolutionarily conserved role of the pathway in innate immunity. WIREs RNA 2018, 9:e1441. doi: 10.1002/wrna.1441 This article is categorized under: Translation > Translation Regulation RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes Regulatory RNAs/RNAi/Riboswitches > Riboswitches.

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

“…127,128 Moreover, coregulation occurs as the GAIT complex and glycolysis are activated via mTORC1 and S6K1. 129 Translational silencing of IFN-γ can occur via GAPDH binding to AU-rich elements within the 3'UTR of IFN-γ mRNA, repressing expression in CD4 T cells. 127 Meanwhile, others have shown lactate dehydrogenase A is induced to support aerobic glycolysis and epigenetic changes, controlling IFN-γ expression independent of 3′UTR-mediated mechanisms in CD4 + T cells but not in CD8 + T cells.…”

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

“…This promotes the dissociation of EPRS from the MSC, and subsequently promotes its association with the IFN-γ-activated inhibition of translation (GAIT) complex [32]. The heterotetrameric GAIT complex, including EPRS, binds to distinct 3′-untranslated regions of mRNAs involved in chronic inflammation to suppress their translation [33]. RNA virus infectionspecific phosphorylation was also identified at the EPRS Ser990 residue [20].…”

“…Alteration of TRS and AlaRS expression does not markedly alter global protein synthesis [38]. PTMs located in the additional domains of vertebrate ARSs do not affect aminoacylation of these enzymes [20,33]. However, PTMs of residues located in the catalytic core domain can influence the enzymatic activities of ARSs.…”

Regulation of yeast RPL22B splicing depends on intact pre-mRNA context of the intron

“…As it was found, Rpl26 bound p53 mRNA through its 5' untranslated region (5'UTR), which stimulated translation and thus contributed to the regulation of DNA-damage response (Takagi et al, 2005). Rpl13a, upon IFN-γ activated phosphorylation, was released from ribosomes and translationally inhibited several groups of mRNAs as part of the GAIT system, which directed transcript selective translational control in myeloid cells (Arif et al, 2018;Mukhopadhyay et al, 2008).…”