Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 6, Pages 1832-1837Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0809632106
Keywords
mouse genetics; phosphatase regulation; protein synthesis; unfolded protein response
Categories
Funding
- National Institutes of Health [DK47119, ES08681, DK42394, HL52173, PO1 HL057346]
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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(alpha P), 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 PPP1 class to eIF2(alpha P), 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(-/-) 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(S51A), that prevents regulated phosphorylation of eIF2 alpha. These findings reveal that the essential process of eIF2(alpha P) dephosphorylation is the predominant role of PPP1R15 proteins in mammalian development.
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