title: Moco biosynthesis and the ATAC acetyltransferase engage translation initiation by inhibiting latent PKR activity.
abstract: 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 a component of the Ada Two A containing (ATAC) acetyltransferase complex. Here, we show that human MPT synthase 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 2α (eIF2α). The suppression of eIF2α 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.
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA tas@stowers.org.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Suganuma
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Selene K
authors.initials: SK
authors.lastname: Swanson
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Washburn
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Workman
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003067:Coenzymes / Q000096:biosynthesis*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008667:Metalloproteins / Q000096:biosynthesis*; D000090006:Molybdenum Cofactors; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011621:Pteridines; D013466:Sulfurtransferases / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D000123:Acetyltransferases; D003067:Coenzymes; D015852:Eukaryotic Initiation Factor-2; D020662:Guanine Nucleotide Exchange Factors; D048031:JNK Mitogen-Activated Protein Kinases; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D011621:Pteridines; D013466:Sulfurtransferases; D019892:eIF-2 Kinase; C022261:molybdopterin; C000602769:EIF2AK2 protein, human; C085585:molybdopterin synthase
keywords: ATAC; MPT synthase; Moco biosynthesis; PKR