Molybdenum cofactor(Moco)biosynthesis is linked to c-Jun N-terminal kinase(JNK)signaling in Drosophila through MoaE,a molybdopterin(MPT)synthase subunit that is also acomponent of theAdaTwoAcontaining(ATAC)acetyltrans...Molybdenum cofactor(Moco)biosynthesis is linked to c-Jun N-terminal kinase(JNK)signaling in Drosophila through MoaE,a molybdopterin(MPT)synthase subunit that is also acomponent of theAdaTwoAcontaining(ATAC)acetyltransferasecomplex.Here,weshow thathumanMPTsynthase and ATAC inhibited PKR,a double-stranded RNA-dependent protein kinase,to facilitate translation initiation of iron-responsive mRNA.MPT synthase and ATAC directly interacted with PKR and suppressed latent autophosphorylation of PKR and its downstream phosphorylation of JNK and eukaryotic initiation factor 2a(eIF2a).The suppression of eIF2a phosphorylation via MPT synthase and ATAC prevented sequestration of the guanine nucleotide exchange factor eIF2B,which recycles eIF2-GDP to eIF2-GTP,resulting in the promotion of translation initiation.Indeed,translation of the iron storage protein,ferritin,was reduced in the absence of MPT synthase or ATAC subunits.Thus,MPT synthase and ATAC regulate latent PKR signaling and link transcription and translation initiation.展开更多
基金supported by private funding fromthe Stowers Institute for Medical Research to the Workman laboratory.
文摘Molybdenum cofactor(Moco)biosynthesis is linked to c-Jun N-terminal kinase(JNK)signaling in Drosophila through MoaE,a molybdopterin(MPT)synthase subunit that is also acomponent of theAdaTwoAcontaining(ATAC)acetyltransferasecomplex.Here,weshow thathumanMPTsynthase and ATAC inhibited PKR,a double-stranded RNA-dependent protein kinase,to facilitate translation initiation of iron-responsive mRNA.MPT synthase and ATAC directly interacted with PKR and suppressed latent autophosphorylation of PKR and its downstream phosphorylation of JNK and eukaryotic initiation factor 2a(eIF2a).The suppression of eIF2a phosphorylation via MPT synthase and ATAC prevented sequestration of the guanine nucleotide exchange factor eIF2B,which recycles eIF2-GDP to eIF2-GTP,resulting in the promotion of translation initiation.Indeed,translation of the iron storage protein,ferritin,was reduced in the absence of MPT synthase or ATAC subunits.Thus,MPT synthase and ATAC regulate latent PKR signaling and link transcription and translation initiation.
