dos 1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2a) dephosphorylation in mammalian development

Diverse cellular stress responses are linked to phosphorylation of serine 51 on the alpha subunit of translation initiation factor 2. The resultant attenuation of protein synthesis and activation of gene expression figure heavily in the adaptive response to stress, but dephosphorylation of eIF2(aP),...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (6), p.1832-1837
Main Authors: Harding, Heather P, Zhang, Yuhong, Scheuner, Donalyn, Chen, Jane-Jane, Kaufman, Randal J, Ron, David
Format: Article
Language:English
Subjects:
Catalytic subunits
Dephosphorylation
Embryos
Erythropoiesis
GADD34 protein
Gene expression
Gestation
Growth rate
Initiation factor eIF-2
Lethality
Mutation
Phosphorylation
Protein biosynthesis
Serine
Signal transduction
Stress
Translation initiation factor 2
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Summary:Diverse cellular stress responses are linked to phosphorylation of serine 51 on the alpha subunit of translation initiation factor 2. The resultant attenuation of protein synthesis and activation of gene expression figure heavily in the adaptive response to stress, but dephosphorylation of eIF2(aP), which terminates signaling in this pathway, is less well understood. GADD34 and CReP, the products of the related mammalian genes Ppp1r15a and Ppp1r15b, can recruit phosphatase catalytic subunits of the dos 1 class to eIF2(aP), but the significance of their contribution to its dephosphorylation has not been explored systematically. Here we report that unlike Ppp1r15a mutant mice, which are superficially indistinguishable from wild type, Ppp1r15b super(-/-) mouse embryos survive gestation but exhibit severe growth retardation and impaired erythropoiesis, and loss of both Ppp1r15 genes leads to early embryonic lethality. These loss-of-function phenotypes are rescued by a mutation, Eif2a super(S51A), that prevents regulated phosphorylation of eIF2a. These findings reveal that the essential process of eIF2(aP) dephosphorylation is the predominant role of dos 1R15 proteins in mammalian development.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0809632106