The GAIT system: a gatekeeper of inflammatory gene expression.
Functionally related genes are coregulated by specific RNA-protein interactions that direct transcript-selective translational control. In myeloid cells, interferon (IFN)-gamma induces formation of the heterotetrameric, IFN-gamma-activated inhibitor of translation (GAIT) complex comprising glutamyl-prolyl tRNA synthetase (EPRS), NS1-associated protein 1 (NSAP1), ribosomal protein L13a and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This complex binds defined 3' untranslated region elements within a family of inflammatory mRNAs and suppresses their translation. IFN-gamma-dependent phosphorylation, and consequent release of EPRS and L13a from the tRNA multisynthetase complex and 60S ribosomal subunit, respectively, regulates GAIT complex assembly. EPRS recognizes and binds target mRNAs, NSAP1 negatively regulates RNA binding, and L13a inhibits translation initiation by binding eukaryotic initiation factor 4G. Repression of a post-transcriptional regulon by the GAIT system might contribute to the resolution of chronic inflammation.
Mukhopadhyay
Rupak
R
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, OH 44195, USA.
Jia
Jie
J
Arif
Abul
A
Ray
Partho Sarothi
PS
Fox
Paul L
PL
D020413:3' Untranslated Regions / Q000378:metabolism; D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism; D000818:Animals; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism
D020413:3' Untranslated Regions; D039603:Eukaryotic Initiation Factor-4G; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; D007371:Interferon-gamma; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000604:Amino Acyl-tRNA Synthetases; C415462:glutamyl-prolyl-tRNA synthetase