GCN2 adapts protein synthesis to scavenging-dependent growth

The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages

“…EM analysis of liver Mφ revealed impaired maturation of lysosomal vesicles in GCN2 −/− mice. This is consistent with a recent report that demonstrated that in response to amino acid deprivation, GCN2 controls the expression of lysosomal genes such as hydrolases ( 63 ). Importantly, NRF2 ChIP-seq analysis in GCN2 +/+ and GCN2 −/− cells demonstrated that GCN2 regulates several NRF2 targets that are involved in iron recycling and lysosomal function.…”

The amino acid sensor GCN2 suppresses terminal oligopyrimidine (TOP) mRNA translation via La-related protein 1 (LARP1)

“…Our study reveals a novel link between amino acid sensor GCN2 and regulation of TOP mRNA translation via control of LARP1. Previous studies have demonstrated that lack of GCN2 promotes translation of specific TOP mRNAs through a yet unidentified mechanism 50 . While Damgaard et al proposed that GCN2 regulates translation of TOP J o u r n a l P r e -p r o o f 11 mRNAs via stress granule (SG)-associated TIA-1 and TIAR proteins 11 , other studies proposed alternative mechanisms such as a GCN2-eIF2α-dependent 51 , GCN2-dependent eIF2-independent 52 , or indirectly through regulation of the mTORC1 pathway 53 34 .…”

“…Our study reveals a novel link between the amino acid sensor GCN2 and the regulation of TOP mRNA translation through modulation of LARP1 mRNA, protein levels, and association with stalled ribosomes. Previous studies have demonstrated that lack of GCN2 promotes translation of specific TOP mRNAs through a yet unidentified mechanism ( 50 ). While Damgaard et al.…”

“…Trimmed reads were then aligned to the mouse reference genome mm10 using BWA v0.7.12 59 . Peaks were called using MACS v2.1.0 software and default parameters (mfold= [5,50]; FDR cutoff=0.05, --nomodel) using sequenced libraries of either WT or GCN2 KO input DNA as control 60 . The regions defined by the peak summit ±150bp were used for downstream analysis.…”

A cell-based chemical-genetic screen for amino acid stress response inhibitors reveals torins reverse stress kinase GCN2 signaling

“…In our model, stalled ribosomes are central to GCN2 activation and should puromycin cause ribosome dissociated, the GCN2 activity would be suppressed independent of amino acid amounts. Second, the exact mechanism of GCN2 activation requires structural illumination combined with a knowledge of the dynamic relationship between amounts of amino acids required in different cellular compartments; different cells have substantially different ways of harvesting or mobilizing amino acids depending on their needs ( 16 , 19 , 20 , 72 ). Such pathways have been uncovered especially in different cancer cell types.…”