Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2alpha) 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(alphaP), 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(alphaP), 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 eIF2alpha. These findings reveal that the essential process of eIF2(alphaP) dephosphorylation is the predominant role of PPP1R15 proteins in mammalian development.
Harding
Heather P
HP
Kimmel Center for Biology and Medicine of the Skirball Institute and the Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Zhang
Yuhong
Y
Scheuner
Donalyn
D
Chen
Jane-Jane
JJ
Kaufman
Randal J
RJ
Ron
David
D
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D004622:Embryo, Mammalian; D004920:Erythropoiesis; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism* / Q000502:physiology; D005260:Female; D005313:Fetal Death; D055786:Gene Knockout Techniques; D006130:Growth Disorders; D048788:Growth and Development / Q000235:genetics; D051379:Mice; D054645:Protein Phosphatase 1 / Q000235:genetics*
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; C513256:Ppp1r15a protein, mouse; C480350:Ppp1r15b protein, mouse; D054645:Protein Phosphatase 1