Journal
MOLECULAR CELL
Volume 29, Issue 6, Pages 679-690Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2008.01.010
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Funding
- NHLBI NIH HHS [R01 HL067725-04, P01 HL076491, P01 HL029582, P01 HL29582, R01 HL067725, P01 HL076491-050006, R01 HL67725, P01 HL76491, P01 HL029582-220003] Funding Source: Medline
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The heterotetrameric GAIT complex suppresses translation of selected mRNAs in interferon-gamma-activated monocytic cells. Specificity is dictated by glutarnyl-prolyl tRNA synthetase (EPRS) binding to a 3'UTR element in target mRNAs. EPRS consists of two synthetase cores joined by a linker containing three WHEP domains of unknown function. Here we show the critical role of EPRS WHEP domains in targeting and regulating GAIT complex binding to RNA. The upstream WHEP pair directs high-affinity binding to GAIT element-bearing mRNAs, while the overlapping, downstream pair binds NSAP1, which inhibits mRNA binding. Interaction of EPRS with ribosomal protein L13a and GAPDH induces a conformational switch that rescues mRNA binding and restores translational control. Total reconstitution from purified components indicates that the four GAIT proteins are necessary and sufficient for self-assembly of a functional complex. Our results establish the essentiality of WHEP domains in the noncanonical function of EPRS in regulating inflammatory gene expression.
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