期刊
GENES & DEVELOPMENT
卷 25, 期 9, 页码 917-929出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.623011
关键词
bone marrow failure syndromes; ribosome assembly; eIF6; human genetics; leukemia; ribosomopathy; NMR
资金
- Leukemia and Lymphoma Research
- Association for International Cancer Research
- Sylvia Aitkin Trust
- Medical Research Council
- MDS Foundation
- Leukemia and Lymphoma Society of America
- Shwachman-Diamond Support UK
- Ted's Gang
- Tesni Parry Memorial Fund
- Cambridge NIHR Biomedical Research Center
- Cancer Research UK
- Institut de Veille Sanitaire
- Inserm
- Association Laurette Fugain
- Association Sportive de Saint Quentin Fallavier
- Canadian Institutes of Health Research (CIHR) [MOP-102629]
- National Institutes of Health (NIH) [1R01HG005853-01]
- Ontario Research Fund [ORF-GL2, GL2-01-22]
- Medical Research Council [MC_U105161083, MC_U105178805] Funding Source: researchfish
- MRC [MC_U105161083, MC_U105178805] Funding Source: UKRI
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.
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