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RNA helicase EIF4A1-mediated translation is essential for the GC response

ABSTRACT: EIF4A1 and cofactors EIF4B and EIF4H have been well characterised in cancers, including B cell malignancies, for their ability to promote the translation of oncogenes with structured 5’ untranslated regions. However, very little is known of their roles in non-malignant cells. Using mouse models to delete Eif4a1, Eif4b or Eif4h in B cells we show that EIF4A1, but not EIF4B or EIF4H, is essential for B cell development and the germinal centre response. Following B cell activation in vitro, EIF4A1 facilitates an increased rate of protein synthesis, MYC expression and expression of cell cycle regulators. However, EIF4A1-deficient cells remain viable whereas inhibition of EIF4A1 and EIF4A2 by Hippuristanol treatment induces cell death.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, B Cell

SUBMITTER: Andrew Howden

LAB HEAD: Professor Martin Turner

PROVIDER: PXD046710 | Pride | 2023-11-09

REPOSITORIES: Pride

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	AH-10A.raw	Raw
	AH-10B.raw	Raw
	AH-7A.raw	Raw
	AH-7B.raw	Raw
	AH-8A.raw	Raw

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EIF4A1 is essential in B cells by promoting activation-induced translation

Project description:EIF4A1 and cofactors EIF4B and EIF4H have been well characterised in cancers, including B cell malignancies, for their ability to promote the translation of oncogenes with structured 5’ untranslated regions but very little is known of their roles in non-malignant cells. Using mouse models to delete Eif4a1, Eif4b or Eif4h in B cells we show that EIF4A1, but not EIF4B or EIF4H, is essential for B cell development and the germinal centre response. Following activation, EIF4A1 facilitates an increased rate of protein synthesis, MYC expression and expression of cell cycle regulators. However, EIF4A1-deficient cells remain viable whereas Hippuristanol treatment induces cell death.

2023-07-21 | GSE237426 | GEO

Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses - SLC7A5 and SLC7A8 KO

Project description:Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens – including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals, but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 were found to be uniquely pre-primed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine producing capacity of ILC2. Moreover, amino acid determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.

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Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells

Project description:Natural Killer (NK) cells are innate lymphocytes that are key to intrinsic cancer immunosurveillance and an important target for cancer immunotherapy. Understanding fundamental human NK cell metabolism provides opportunities for optimising NK cell therapies. Little is known about how glutamine, an important cell nutrient and carbon source, is utilised by human NK cells. To address this, we performed U13C-glutamine tracing experiments by Liquid Chromatography Mass Spectrometry (LCMS) and Gas Chromatography Mass Spectrometry (GCMS) analysis of human NK cells stimulated with IL-2 for 18 hours to provide a global overview of glutamine usage by these cells. Our results show that glutamine is taken up by resting NK cells and that this increases further upon IL-2 stimulation. Metabolite labelling analysis identified that IL-2 results in greater conversion of glutamine to glutamate, allowing for anaplerotic flux into the TCA cycle. The fate of the glutamine-derived carbons diverged at oxaloacetate (OAA) allowing both bioenergetic and biosynthetic outcomes - some carbons continued around the TCA cycle while others were exported, converted to aspartate and subsequently used for pyrimidine synthesis. Nucleotide synthesis by IL-2 activated NK cells was found to be essential for expression of the activation marker CD69. The data indicate that glutamine is a key nutrient taken up by human NK cells, and that IL-2 drives glutaminolysis. Subsequent glutamate is used to support the TCA cycle, generating energy and providing intermediates for de novo pyrimidine synthesis.

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Iron depletion proteomics of Toxoplasma tachyzoites

Project description:Iron is essential for almost all life as a result of its vital role as a protein cofactor. Toxoplasma must obtain iron from their host cells, but these host cells can employ strategies to restrict pathogen access to this essential nutrient. Here we use quantitative proteomics of Toxoplasma tachyzoites grown for 24 hours in control or iron depleted conditions to understand proteomic adaptation to low iron conditions. We find that iron deprived parasites remodel their proteome profoundly in response to iron depletion, including the downregulation of much of the machinery involved in protein translation.

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eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies

Project description:The amounts of eIF4G and eIF4B were decreased in the vemurafenib-treated sensitive A375 cell line. To find mechanisms behind this decrease, we sought to identify the genes whose expression changes after vemurafenib treatment in A375 cells as compared to Mel624 cells by using microarrays.

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Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing

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2023-09-26 | PXD045562 | Pride

Analysis of Zyxin's interactome and phosphosites in early Xenopus laevis development by Data-Independent Acquisition proteomics

Project description:Protein complexes are key players in development, functioning as molecular machines whose proper assembly is crucial for numerous cellular processes. Their formation at the correct time and location is facilitated by specialized scaffold proteins. A prominent example is the mechanosensitive cytoskeletal protein zyxin. Zyxin is of particular interest due to its role in assembling actin filaments within focal adhesion complexes and transducing signals from the cytoskeleton to the genetic apparatus. In this study, we employed co-immunoprecipitation coupled with mass spectrometry to analyze changes in zyxin-associated protein complexes from lysates of Xenopus frog embryos across three early developmental stages: early gastrulation, early neurulation, and late neural fold stages. Our analysis revealed stage-specific alterations in the isoform repertoires of several established zyxin partners, including components of the focal adhesion complex, transcriptional regulators, and proteins involved in its phosphorylation. We also identified changes in the phosphorylation patterns of different zyxin isoforms. Collectively, these findings provide a valuable resource for elucidating the function of the scaffold protein zyxin and its role in embryonic tissue development. Furthermore, the identification of kinases and caspases within the zyxin interactome suggests its involvement in key signaling pathways related to cell survival and apoptosis. Finally, confirmed interactions with partners such as 14-3-3 proteins, Yap, and TEF-1 highlight the multifaceted role of zyxin in cellular regulation and its potential as a therapeutic target.

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eIF4B preferentially stimulates translation of long mRNAs with structured 5’UTRs and low closed-loop potential but weak dependence on eIF4G

Project description:DEAD-box RNA helicases eIF4A and Ded1 promote translation by resolving mRNA secondary structures that impede preinitiation complex (PIC) attachment to mRNA or scanning. eIF4B is a cofactor for eIF4A but might also function independently of eIF4A. Ribosome profiling of mutants lacking eIF4B or with impaired eIF4A or Ded1 activity revealed that eliminating eIF4B reduces the relative translational efficiencies of many more genes than does inactivation of eIF4A, despite comparable reductions in bulk translation, and few genes display unusually strong requirements for both factors. However, either eliminating eIF4B or inactivating eIF4A preferentially impacts mRNAs with longer, more structured 5’UTRs. These findings reveal an eIF4A-independent role for eIF4B in addition to its function as eIF4A cofactor in promoting PIC attachment or scanning on structured mRNAs. eIF4B, eIF4A, and Ded1 mutations also preferentially impair translation of longer mRNAs in a fashion mitigated by the ability to form closed-loop mRNPs via eIF4F-Pab1 association, suggesting cooperation between closed-loop assembly and eIF4B/helicase functions. Remarkably, depleting eIF4G, the scaffold subunit of eIF4F, preferentially impacts short mRNAs with strong closed-loop potential and unstructured 5’UTRs, exactly the opposite features associated with hyperdependence on the eIF4B/helicases. We propose that short, highly efficient mRNAs preferentially depend on the stimulatory effects of eIF4G-dependent closed-loop assembly.

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