Gene expression profile at Ptpmt1 cardiomyocytes-specific Knockout mcie, Eif2a mutant mice, Gcn2 Knockout mice, and Hri Knockout mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201042 | GEO | 2022/04/21
REPOSITORIES: GEO
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Project description:Gene expression profile at Ptpmt1 cardiomyocytes-specific Knockout mcie, Eif2a mutant mice, Gcn2 Knockout mice, and Hri Knockout mice
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Project description:Cytoplasmic proteotoxicity regulates HRI-dependent phosphorylation of eIF2a via the Hsp70-Bag3 module.
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Project description:Iron and heme play central roles in red blood cell production. However, the mechanisms by which iron and heme levels coordinate erythropoiesis remain incompletely understood. HRI is a heme-regulated kinase that controls translation by phosphorylating eIF2a. Here, we investigate the global impact of iron, heme and HRI on protein translation in vivo in murine primary erythroblasts using ribosome profiling. By defining the underlying changes in translation during iron and HRI deficiencies, we validate known regulators of this process, including Atf4, and identify novel pathways such as co-regulation of ribosomal protein mRNA translation. Surprisingly, we found that heme and HRI pathways, but not iron-regulated pathways, mediate the major protein translational and transcriptional responses to iron deficiency in erythroblasts in vivo and thereby identify previously unappreciated regulators of erythropoiesis. Our genome-wide study uncovers the major impact of the HRI-mediated integrated stress response for the adaptation to iron deficiency anemia.
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Project description:Heme-regulated inhibitorRegulated Inhibitor (HRI) is one of the four mammalian kinases that phosphorylate eIF2α, facilitating a cellular response to stress through the regulation of mRNA translation. Originally identified as a heme sensor in erythroid progenitor cells, HRI has since emerged as a potential therapeutic target in both cancer and neurodegeneration. Here we purified recombinant expressed human HRI and allowed it to autophosphorylate.
2025-06-18 | PXD064940 | Pride
Project description:The RNA-binding protein eIF2A has been implicated in a variety of cellular processes including tumorigenesis. This role has been attributed to its function as alternative translation initiation factor. However, the mechanisms by which eIF2A regulates translation and its contribution to oncogenic transformation are unclear. Here, we shed light on these aspects using a melanoma cell model consisting of the non-tumoral melanocytic cell line MelST and its metastatic counterpart obtained by RasV12 overexpression (MelSTR). Depletion of eIF2A from MelST and MelSTR cells revealed acquired dependencies upon Ras transformation for migration. Surprisingly, analysis of the transcriptome (RNA-Seq) and translatome (ribosome profiling) upon eIF2A depletion showed minor to no changes in translation. RIP-Seq and RT-qPCR furthermore indicate that eIF2A binds mRNA targets in a translation-independent manner. Interestingly, protein interactome analyses point towards a function of eIF2A in cytoskeletal remodeling and indeed we can show that eIF2A localizes to the centrosome and affects its composition and orientation, linking eIF2A with migration. In addition, eIF2A promotes migration in a manner that depends on its RNA-binding activity. Together, these results indicate that eIF2A does not function as a translation factor in melanoma cells, but through a novel function which is based on its RNA-binding activity and its connections to the centrosome.
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Project description:The RNA-binding protein eIF2A has been implicated in a variety of cellular processes including tumorigenesis. This role has been attributed to its function as alternative translation initiation factor. However, the mechanisms by which eIF2A regulates translation and its contribution to oncogenic transformation are unclear. Here, we shed light on these aspects using a melanoma cell model consisting of the non-tumoral melanocytic cell line MelST and its metastatic counterpart obtained by RasV12 overexpression (MelSTR). Depletion of eIF2A from MelST and MelSTR cells revealed acquired dependencies upon Ras transformation for migration. Surprisingly, analysis of the transcriptome (RNA-Seq) and translatome (ribosome profiling) upon eIF2A depletion showed minor to no changes in translation. RIP-Seq and RT-qPCR furthermore indicate that eIF2A binds mRNA targets in a translation-independent manner. Interestingly, protein interactome analyses point towards a function of eIF2A in cytoskeletal remodeling and indeed we can show that eIF2A localizes to the centrosome and affects its composition and orientation, linking eIF2A with migration. In addition, eIF2A promotes migration in a manner that depends on its RNA-binding activity. Together, these results indicate that eIF2A does not function as a translation factor in melanoma cells, but through a novel function which is based on its RNA-binding activity and its connections to the centrosome.
2025-06-27 | GSE279472 | GEO
Project description:The RNA-binding protein eIF2A has been implicated in a variety of cellular processes including tumorigenesis. This role has been attributed to its function as alternative translation initiation factor. However, the mechanisms by which eIF2A regulates translation and its contribution to oncogenic transformation are unclear. Here, we shed light on these aspects using a melanoma cell model consisting of the non-tumoral melanocytic cell line MelST and its metastatic counterpart obtained by RasV12 overexpression (MelSTR). Depletion of eIF2A from MelST and MelSTR cells revealed acquired dependencies upon Ras transformation for migration. Surprisingly, analysis of the transcriptome (RNA-Seq) and translatome (ribosome profiling) upon eIF2A depletion showed minor to no changes in translation. RIP-Seq and RT-qPCR furthermore indicate that eIF2A binds mRNA targets in a translation-independent manner. Interestingly, protein interactome analyses point towards a function of eIF2A in cytoskeletal remodeling and indeed we can show that eIF2A localizes to the centrosome and affects its composition and orientation, linking eIF2A with migration. In addition, eIF2A promotes migration in a manner that depends on its RNA-binding activity. Together, these results indicate that eIF2A does not function as a translation factor in melanoma cells, but through a novel function which is based on its RNA-binding activity and its connections to the centrosome.
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Project description:Eukaryotic initiation factor 2A (eIF2A) is a 65-kDa protein that was first identified in the early 1970s as a factor capable of stimulating initiator methionyl-tRNAi (Met-tRNAMeti) binding to 40S ribosomal subunits in vitro. However, in contrast to the eIF2, which stimulates Met-tRNAMeti binding to 40S ribosomal subunits in a GTP-dependent manner, eIF2A didn't reveal any GTP-dependence, but instead was found to direct binding of the Met-tRNAMeti to 40S ribosomal subunits in a codon-dependent manner. eIF2A appears to be highly conserved across eukaryotic species, suggesting conservation of function in evolution. The yeast Saccharomyces cerevisae eIF2A null mutant revealed no apparent phenotype, however, it was found that in yeast eIF2A functions as a suppressor of internal ribosome entry site (IRES)-mediated translation. It was thus suggested that eIF2A my act by impinging on the expression of specific mRNAs. Subsequent studies in mammalian cell systems implicated eIF2A in non-canonical (non-AUG-dependent) translation initiation events involving near cognate UUG and CUG codons. Yet, the role of eIF2A in cellular functions remains largely enigmatic. As a first step toward characterization of the eIF2A function in mammalian systems in vivo, we have obtained homozygous eIF2A-total knockout (KO) mice, in which a gene trap cassette was inserted between eIF2A exons 1 and 2 disrupting expression of all exons downstream of the insertion. The KO mice strain is viable and to date displays no apparent phenotype. We believe that the eIF2A KO mice strain will serve as a valuable tool for researchers studying non-canonical initiation of translation in vivo.
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Project description:Eukaryotic initiation factor 2A (eIF2A) is a 65 kDa protein that functions in minor initiation pathways, which affect the translation of only a subset of messenger ribonucleic acid (mRNAs), such as internal ribosome entry site (IRES)-containing mRNAs and/or mRNAs harboring upstream near cognate/non-AUG start codons. These non-canonical initiation events are important for regulation of protein synthesis during cellular development and/or the integrated stress response. Selective eIF2A knockdown in cellular systems significantly inhibits translation of such mRNAs, which rely on alternative initiation mechanisms for their translation. However, there exists a gap in our understanding of how eIF2A functions in mammalian systems in vivo (on the organismal level) and ex vivo (in cells). Here, using an eIF2A-knockout (KO) mouse model, we present evidence implicating eIF2A in the biology of aging, metabolic syndrome and central tolerance. We discovered that eIF2A-KO mice have reduced life span and that eIF2A plays an important role in maintenance of lipid homeostasis, the control of glucose tolerance, insulin resistance and also reduces the abundance of B lymphocytes and dendritic cells in the thymic medulla of mice. We also show the eIF2A KO affects male and female mice differently, suggesting that eIF2A may affect sex-specific pathways. Interestingly, our experiments involving pharmacological induction of endoplasmic reticulum (ER) stress with tunicamycin did not reveal any substantial difference between the response to ER stress in eIF2A-KO and wild-type mice. The identification of eIF2A function in the development of metabolic syndrome bears promise for the further identification of specific eIF2A targets responsible for these changes.
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