title: Regulatory effects of programmed cell death 4 (PDCD4) protein in interferon (IFN)-stimulated gene expression and generation of type I IFN responses.
abstract: The precise mechanisms by which the activation of interferon (IFN) receptors (IFNRs) ultimately controls mRNA translation of specific target genes to induce IFN-dependent biological responses remain ill defined. We provide evidence that IFN-α induces phosphorylation of programmed cell death 4 (PDCD4) protein on Ser67. This IFN-α-dependent phosphorylation is mediated by either the p70 S6 kinase (S6K) or the p90 ribosomal protein S6K (RSK) in a cell-type-specific manner. IFN-dependent phosphorylation of PDCD4 results in downregulation of PDCD4 protein levels as the phosphorylated form of PDCD4 interacts with the ubiquitin ligase β-TRCP (β-transducin repeat-containing protein) and undergoes degradation. This process facilitates IFN-induced eukaryotic translation initiation factor 4A (eIF4A) activity and binding to translation initiation factor eIF4G to promote mRNA translation. Our data establish that PDCD4 degradation ultimately facilitates expression of several ISG protein products that play important roles in the generation of IFN responses, including IFN-stimulated gene 15 (ISG15), p21(WAF1/CIP1), and Schlafen 5 (SLFN5). Moreover, engagement of the RSK/PDCD4 pathway by the type I IFNR is required for the suppressive effects of IFN-α on normal CD34(+) hematopoietic precursors and for antileukemic effects in vitro. Altogether, these findings provide evidence for a unique function of PDCD4 in the type I IFN system and indicate a key regulatory role for this protein in mRNA translation of ISGs and control of IFN responses.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kroczynska
authors.forename: Bhumika
authors.initials: B
authors.lastname: Sharma
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eklund
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D039601:Eukaryotic Initiation Factor-4A / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D039603:Eukaryotic Initiation Factor-4G; D007370:Interferon Type I; C114487:PDCD4 protein, human; C498443:Pdcd4 protein, mouse; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D039601:Eukaryotic Initiation Factor-4A