Experimental animal study reveals GCN2 mediates the early hepatic integrated stress response to sulfur amino acid deprivation in mice, highlighting a coordinated metabolic adaptation.
Key Points
To determine the role of the kinase GCN2 in directing the early hepatic integrated stress response and adaptive transcriptional programs during acute dietary sulfur amino acid deprivation.
Monitored temporal integrated stress response dynamics using ATF4-luciferase reporter mice during short-term sulfur amino acid deprivation.
Evaluated the distinct contributions of GCN2 and PERK via genetic deletion and pharmacological inhibition in vivo and ex vivo.
Profiled hepatic downstream gene expression programs involved in amino acid transport, tRNA synthesis, autophagy, and metabolic adaptation.
Sulfur amino acid deprivation rapidly activated the hepatic eIF2α-ATF4 signaling pathway within 3 hours.
Genetic deletion or pharmacological blockade of GCN2 eliminated early eIF2α phosphorylation and ATF4 target gene induction, while PERK was dispensable.
GCN2 coordinated multiple transcriptional programs including amino acid transport, serine biosynthesis, and glutathione degradation, whereas Fgf21 induction occurred independently of GCN2.