title: Translational homeostasis via the mRNA cap-binding protein, eIF4E.
abstract: Translational control of gene expression plays a key role in many biological processes. Consequently, the activity of the translation apparatus is under tight homeostatic control. eIF4E, the mRNA 5' cap-binding protein, facilitates cap-dependent translation and is a major target for translational control. eIF4E activity is controlled by a family of repressor proteins, termed 4E-binding proteins (4E-BPs). Here, we describe the surprising finding that despite the importance of eIF4E for translation, a drastic knockdown of eIF4E caused only minor reduction in translation. This conundrum can be explained by the finding that 4E-BP1 is degraded in eIF4E-knockdown cells. Hypophosphorylated 4E-BP1, which binds to eIF4E, is degraded, whereas hyperphosphorylated 4E-BP1 is refractory to degradation. We identified the KLHL25-CUL3 complex as the E3 ubiquitin ligase, which targets hypophosphorylated 4E-BP1. Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination.
authors.affiliation: Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yanagiya
authors.forename: Eigo
authors.initials: E
authors.lastname: Suyama
authors.forename: Hironori
authors.initials: H
authors.lastname: Adachi
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Svitkin
authors.forename: Pedro
authors.initials: P
authors.lastname: Aza-Blanc
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Imataka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mikami
authors.forename: Yvan
authors.initials: Y
authors.lastname: Martineau
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics* / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D039381:RNA Cap-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D010750:Phosphoproteins; D039381:RNA Cap-Binding Proteins; D025801:Ubiquitin