After binding uncharged tRNA and autophosphorylating, EIF2AK4 (GCN2) phosphorylates EIF2S1 (eIF2 alpha subunit) on serine-52 (serine-51 in the rabbit homolog, inferred from mouse homologs and yeast homologs), which inhibits the guanine nucleotide exchange factor eIF2B, impairs exchange of GDP for GTP, and reduces recycling of EIF2 for initiation of translation. This causes downregulation of translation of most mRNAs, however translation of certain mRNAs possessing upstream ORFs, such as ATF4, is upregulated (inferred from mouse homologs and yeast homologs).