Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2α) dephosphorylation in mammalian development

Harding, Heather P.; Zhang, Yuhong; Scheuner, Donalyn; Chen, Jane-Jane; Kaufman, Randal J.; Ron, David

doi:10.1073/pnas.0809632106

Cited by 240 publications

(231 citation statements)

References 38 publications

(51 reference statements)

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“…The repressed transcription of CSAD may thus deprive the cell of a part of its antioxidant defense. The last transcript involved in the response to stress encodes a homolog of the protein phosphatase 1 regulatory subunit 15B (Ppp1r15b) that targets the translation initiation factor 2 alpha (eIF2α) (Harding et al 2009). Phosphorylation by stress-sensing kinases makes eIF less able to initiate translation, and so the cell builds fewer proteins and conserves more of its resources during times of stress like starvation or exposure to toxins (Chambers et al 2015).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic responses of the endangered freshwater mussel Margaritifera margaritifera to trace metal contamination in the Dronne River, France

Bertucci

Pierron

Thébault

et al. 2017

Environ Sci Pollut Res

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The freshwater pearl mussel Margaritifera margaritifera is one of the most threatened freshwater bivalves worldwide. In this study, we aimed (i) to study the processes by which water quality might affect freshwater mussels in situ and (ii) to provide insights into the ecotoxicological significance of water pollution to natural populations in order to provide necessary information to enhance conservation strategies. M. margaritifera specimens were sampled in two close sites located upstream or downstream from an illegal dumping site. The renal transcriptome of these animals was assembled and gene transcription determined by RNA-seq. Correlations between transcription levels of each single transcript and the bioaccumulation of nine trace metals, age (estimated by sclerochronology), and condition index were determined in order to identify genes likely to respond to a specific factor. Amongst the studied metals, Cr, Zn, Cd, and Ni were the main factors correlated with transcription levels, with effects on translation, apoptosis, immune response, response to stimulus, and transport pathways.However, the main factor explaining changes in gene transcription appeared to be the age of individuals with a negative correlation with the transcription of retrotransposon-related genes. To investigate this effect further, mussels were classified into three age classes. In young, middle-aged and old animals, transcription levels were mainly explained by Cu, Zn and age, respectively. This suggests differences in the molecular responses of this species to metals during its lifetime that must be better assessed in future ecotoxicology studies.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic responses of the endangered freshwater mussel Margaritifera margaritifera to trace metal contamination in the Dronne River, France

Bertucci

Pierron

Thébault

et al. 2017

Environ Sci Pollut Res

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“…In mammalian cells, the specific dephosphorylation of eIF2α is mediated by the GADD34-PP1 and CReP-PP1 complexes (7,8,15). However, no homologs of GADD34 or CReP are found in yeast.…”

Section: Gadd34 Promotesmentioning

confidence: 99%

“…Likewise, the Herpes simplex virus (HSV) γ34.5 protein (16) and the African swine fever virus (ASFV) DP71L protein (17), which both share sequence similarity with GADD34 and CReP, recruit PP1 to dephosphorylate eIF2α in infected cells. Whereas the interaction of PP1 with GADD34, CReP, γ34.5, and DP71L has been shown to depend on the RVxF motif (7,8,(15)(16)(17), it remains to be determined how these regulatory subunits direct PP1 to specifically dephosphorylate eIF2α.…”

mentioning

confidence: 99%

“…In addition to GADD34, mammalian cells encode a constitutively expressed protein named CReP (PPP1R15B) that also interacts with PP1 and is responsible for maintaining the basal levels of eIF2α phosphorylation in unstressed cells (15). Likewise, the Herpes simplex virus (HSV) γ34.5 protein (16) and the African swine fever virus (ASFV) DP71L protein (17), which both share sequence similarity with GADD34 and CReP, recruit PP1 to dephosphorylate eIF2α in infected cells.…”

mentioning

confidence: 99%

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An eIF2α-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2α

Rojas

Vasconcelos

Dever

2015

Proc. Natl. Acad. Sci. U.S.A.

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Transient protein synthesis inhibition, mediated by phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α), is an important protective mechanism cells use during stress conditions. Following relief of the stress, the growth arrest and DNA damage-inducible protein GADD34 associates with the broadly acting serine/threonine protein phosphatase 1 (PP1) to dephosphorylate eIF2α. Whereas the PP1-binding motif on GADD34 has been defined, it remains to be determined how GADD34 directs PP1 to specifically dephosphorylate eIF2α. In this report, we map a novel eIF2α-binding motif to the C terminus of GADD34 in a region distinct from where PP1 binds to GADD34. This motif is characterized by the consensus sequence Rx [Gnl], where capital letters are preferred and x is any residue. Point mutations altering the eIF2α-binding motif impair the ability of GADD34 to interact with eIF2α, promote eIF2α dephosphorylation, and suppress PKR toxicity in yeast. Interestingly, this eIF2α-docking motif is conserved among viral orthologs of GADD34, and is necessary for the proteins produced by African swine fever virus, Canarypox virus, and Herpes simplex virus to promote eIF2α dephosphorylation. Taken together, these data indicate that GADD34 and its viral orthologs direct specific dephosphorylation of eIF2α by interacting with both PP1 and eIF2α through independent binding motifs.

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“…In some experiments, pcDNA3.CD2-heIF2a-S51A encoding a dominant-negative mutant of eIF2a (eIF2a-DN) (provided by Dr David Ron, University of Cambridge) 29 or pcDNA3.1-GADD34 coding for growth arrest and DNA damage gene 34 (GADD34) (provided by Dr Takeshi Omasa, Osaka University) 30 was co-transfected to evaluate involvement of eIF2a. pGL2-F-1005/ þ 93Smad1 that introduces a luciferase gene under the control of the Smad1 gene promoter (provided by Dr Yuewen Gong, University of Manitoba) 31 was also used to evaluate the effect of 3 0 -deoxyadenosine.…”

Section: Reporter Assaymentioning

confidence: 99%

Blockade of Smad signaling by 3′-deoxyadenosine: a mechanism for its anti-fibrotic potential

Johno

Nakajima

et al. 2013

Laboratory Investigation

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Cordyceps militaris has been used in Eastern countries for the treatment of various diseases including chronic kidney diseases. However, there are no reports that identified its active entities and molecular mechanisms underlying its therapeutic effectiveness. 3 0 -Deoxyadenosine is a major nucleoside derivative isolated from C. militaris. Some reports suggested that both C. militaris and 3 0 -deoxyadenosine have anti-inflammatory and anti-fibrotic effects. In the present report, we investigated whether and how 3 0 -deoxyadenosine interferes with fibrogenic processes in the kidney. For this purpose, we examined effects of 3 0 -deoxyadenosine on the expression of collagens triggered by transforming growth factor-b (TGF-b1) and bone morphogenetic protein-4 (BMP-4), especially focusing on the regulation of Smad signaling in vitro and in vivo. We found that 3 0 -deoxyadenosine suppressed expression of collagens induced by TGF-b1 and BMP-4 dose dependently. This suppression occurred at the transcriptional level and was correlated with blunted activation of the CAGA box and the BMP-responsive element. The suppressive effect on the TGF-b/BMP signaling was mediated mainly by adenosine transporter and partially by the A3 adenosine receptor, but not A1/A2 adenosine receptors. 3 0 -Deoxyadenosine reduced levels of both phosphorylated and total Smad proteins (Smad1, 2 and 3) dose dependently. It was mainly ascribed to transcriptional suppression, but not to enhanced protein degradation and eIF2a-mediated translational suppression. Consistent with the in vitro results, in vivo administration with 3 0 -deoxyadenosine reduced the levels of phosphorylated and total Smad proteins, as well as the levels of Smad mRNAs, in the kidney subjected to unilateral ureteral obstruction. It was associated with blunted induction of type I collagen and a-smooth muscle actin, a decrease in the number of interstitial myofibroblasts and reduced fibrotic area. These results suggest that 3 0 -deoxyadenosine interferes with the TGF-b and BMP signaling via downregulation of Smads, which may underlie the anti-fibrotic effect of this agent. 3 0 -Deoxyadenosine may be useful for therapeutic intervention in various TGF-b-related fibrotic disorders.

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Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2α) dephosphorylation in mammalian development

Cited by 240 publications

References 38 publications

Transcriptomic responses of the endangered freshwater mussel Margaritifera margaritifera to trace metal contamination in the Dronne River, France

Transcriptomic responses of the endangered freshwater mussel Margaritifera margaritifera to trace metal contamination in the Dronne River, France

An eIF2α-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2α

Blockade of Smad signaling by 3′-deoxyadenosine: a mechanism for its anti-fibrotic potential

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