title: Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome.
abstract: Removal of the assembly factor eukaryotic initiation factor 6 (eIF6) is critical for late cytoplasmic maturation of 60S ribosomal subunits. In mammalian cells, the current model posits that eIF6 release is triggered following phosphorylation of Ser 235 by activated protein kinase C. In contrast, genetic studies in yeast indicate a requirement for the ortholog of the SBDS (Shwachman-Bodian-Diamond syndrome) gene that is mutated in the inherited leukemia predisposition disorder Shwachman-Diamond syndrome (SDS). Here, by isolating late cytoplasmic 60S ribosomal subunits from Sbds-deleted mice, we show that SBDS and the GTPase elongation factor-like 1 (EFL1) directly catalyze eIF6 removal in mammalian cells by a mechanism that requires GTP binding and hydrolysis by EFL1 but not phosphorylation of eIF6 Ser 235. Functional analysis of disease-associated missense variants reveals that the essential role of SBDS is to tightly couple GTP hydrolysis by EFL1 on the ribosome to eIF6 release. Furthermore, complementary NMR spectroscopic studies suggest unanticipated mechanistic parallels between this late step in 60S maturation and aspects of bacterial ribosome disassembly. Our findings establish a direct role for SBDS and EFL1 in catalyzing the translational activation of ribosomes in all eukaryotes, and define SDS as a ribosomopathy caused by uncoupling GTP hydrolysis from eIF6 release.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. ajw@mrc-lmb.cam.ac.uk
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Finch
authors.forename: Christine
authors.initials: C
authors.lastname: Hilcenko
authors.forename: Nicolas
authors.initials: N
authors.lastname: Basse
authors.forename: Lesley F
authors.initials: LF
authors.lastname: Drynan
authors.forename: Beatriz
authors.initials: B
authors.lastname: Goyenechea
authors.forename: Tobias F
authors.initials: TF
authors.lastname: Menne
authors.forename: Africa
authors.initials: A
authors.lastname: González Fernández
authors.forename: Paul
authors.initials: P
authors.lastname: Simpson
authors.forename: Clive S
authors.initials: CS
authors.lastname: D'Santos
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.forename: Jean
authors.initials: J
authors.lastname: Donadieu
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Michael
authors.initials: M
authors.lastname: Costanzo
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.forename: Andrew N
authors.initials: AN
authors.lastname: McKenzie
authors.forename: Stefan M V
authors.initials: SM
authors.lastname: Freund
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Warren
mesh_terms: D000818:Animals; D001855:Bone Marrow Diseases / Q000235:genetics / Q000503:physiopathology; D002384:Catalysis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics / Q000503:physiopathology; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008068:Lipomatosis; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009154:Mutation; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054683:Ribosome Subunits, Large, Eukaryotic; D012270:Ribosomes / Q000473:pathology*; D000081003:Shwachman-Diamond Syndrome
chemical_list: C109284:EIF6 protein, human; D039642:Eukaryotic Initiation Factors; C115811:Itgb4bp protein, mouse; D010448:Peptide Initiation Factors; D011506:Proteins; C470521:SBDS protein, human; C513661:Sbds protein, mouse; D006160:Guanosine Triphosphate