The Membrane Stress Response Buffers Lethal Effects of Lipid Disequilibrium by Reprogramming the Protein Homeostasis Network

Thibault, Guillaume; Shui, Guanghou; Kim, Woong; McAlister, Graeme C.; Ismail, Nurzian; Gygi, Steven P.; Wenk, Markus R.; Ng, Davis

doi:10.1016/j.molcel.2012.08.016

Cited by 143 publications

(292 citation statements)

References 59 publications

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“…A previous analysis suggests that this is not the case (Thibault et al, 2012). However, in this study a general luminal Fig.…”

Section: Identification Of Novel Genes Required For Mrna Localizationcontrasting

confidence: 59%

“…To compensate for an imbalance in the PtdEtn:PtdCho ratio, cells alter their proteome and increase the synthesis of proteins involved in stress-response pathways, including the unfolded protein response, the ER-associated degradation pathway and the induction of heat-shock proteins (Thibault et al, 2012). However, we do not believe that these proteome changes are directly related to mRNA mislocalization, as loss of Opi3p, the second methyltransferase required for PtdCho biosynthesis, leads to very similar proteome changes (Thibault et al, 2012) but not to a defect in WSC2 localization, indicating a specific role of Cho2p and of its substrate, PtdEtn. The stronger binding of She2p to liposomes with an increasing PtdEtn content supports a more specific role of PtdEtn.…”

Section: Discussionmentioning

confidence: 99%

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Yeast phospholipid biosynthesis is linked to mRNA localization

Hermesh

Genz

Yofe

et al. 2014

Journal of Cell Science

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Regulation of the localization of mRNAs and local translation are universal features in eukaryotes and contribute to cellular asymmetry and differentiation. In Saccharomyces cerevisiae, localization of mRNAs that encode membrane proteins requires the She protein machinery, including the RNA-binding protein She2p, as well as movement of the cortical endoplasmic reticulum (cER) to the yeast bud. In a screen for ER-specific proteins necessary for the directional transport of WSC2 and EAR1 mRNAs, we have identified enzymes that are involved in phospholipid metabolism. Loss of the phospholipid methyltransferase Cho2p, which showed the strongest impact on mRNA localization, disturbs mRNA localization, as well as ER morphology and segregation, owing to an increase in the amount of cellular phosphatidylethanolamine (PtdEtn). Mislocalized mRNPs containing She2p colocalize with aggregated cER structures, suggestive of the entrapment of mRNA and She2p by the elevated PtdEtn level. This was confirmed by the elevated binding of She2p to PtdEtn-containing liposomes. These findings underscore the importance of ER membrane integrity in mRNA transport.

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“…A previous analysis suggests that this is not the case (Thibault et al, 2012). However, in this study a general luminal Fig.…”

Section: Identification Of Novel Genes Required For Mrna Localizationcontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Yeast phospholipid biosynthesis is linked to mRNA localization

Hermesh

Genz

Yofe

et al. 2014

Journal of Cell Science

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“…Lipids comprise 50% of membrane mass and they are also critical components of signalling pathways. Synthesizing membranes of the correct composition is critical for cell function (52,53). In mammalian cells, cholesterol, phospholipids, and sphingolipids are the major lipid constituents of cell membranes.…”

Section: Lipidsmentioning

confidence: 99%

The redox requirements of proliferating mammalian cells

Hosios

Heiden

2018

Journal of Biological Chemistry

112

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Cell growth and division requires nutrients, and proliferating cells use a variety of sources to acquire the amino acids, lipids, and nucleotides that support macromolecule synthesis. Lipids are more reduced than other nutrients, whereas nucleotides and amino acids are typically more oxidized. Cells must therefore generate reducing and oxidizing (redox) equivalents to convert consumed nutrients into biosynthetic precursors. To that end, redox cofactor metabolism plays a central role in meeting cellular redox requirements. In this review, we highlight the biosynthetic pathways that involve redox reactions and discuss their integration with metabolism in proliferating mammalian cells.

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“…The absence of CHO2 renders yeast cells dependent on the UPR for survival (42,44), suggesting that CHO2 contributes to ER homeostasis. Consistent with this, CHO2 deletion shows an aggravating interaction with the loss of EMC genes in terms of yeast growth (39).…”

Section: Identification Of a New Inhibitor Of Fungal Growthmentioning

confidence: 99%

“…Unfolded proteins are sensed by the ER transmembrane sensor Ire1, which triggers the synthesis of Hac1, a transcription factor. Hac1 translocates to the nucleus and upregulates the expression of chaperones, folding enzymes, and other proteins that support ER function (44,50). Since ERAD mutants are hypersensitive to sr7575 and ERAD capacity can be regulated by the UPR, we were surprised to find that neither HAC1 nor IRE1 was identified in the sr7575 chemogenomic screen.…”

Section: Identification Of a New Inhibitor Of Fungal Growthmentioning

confidence: 99%

The Toxicity of a Novel Antifungal Compound Is Modulated by Endoplasmic Reticulum-Associated Protein Degradation Components

Raj

Krishnan

Askew

et al. 2016

Antimicrob Agents Chemother

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iIn a search for new antifungal compounds, we screened a library of 4,454 chemicals for toxicity against the human fungal pathogen Aspergillus fumigatus. We identified sr7575, a molecule that inhibits growth of the evolutionary distant fungi A. fumigatus, Cryptococcus neoformans, Candida albicans, and Saccharomyces cerevisiae but lacks acute toxicity for mammalian cells. To gain insight into the mode of inhibition, sr7575 was screened against 4,885 S. cerevisiae mutants from the systematic collection of haploid deletion strains and 977 barcoded haploid DAmP (decreased abundance by mRNA perturbation) strains in which the function of essential genes was perturbed by the introduction of a drug resistance cassette downstream of the coding sequence region. Comparisons with previously published chemogenomic screens revealed that the set of mutants conferring sensitivity to sr7575 was strikingly narrow, affecting components of the endoplasmic reticulum-associated protein degradation (ERAD) stress response and the ER membrane protein complex (EMC). ERAD-deficient mutants were hypersensitive to sr7575 in both S. cerevisiae and A. fumigatus, indicating a conserved mechanism of growth inhibition between yeast and filamentous fungi. Although the unfolded protein response (UPR) is linked to ERAD regulation, sr7575 did not trigger the UPR in A. fumigatus and UPR mutants showed no enhanced sensitivity to the compound. The data from this chemogenomic analysis demonstrate that sr7575 exerts its antifungal activity by disrupting ER protein quality control in a manner that requires ERAD intervention but bypasses the need for the canonical UPR. ER protein quality control is thus a specific vulnerability of fungal organisms that might be exploited for antifungal drug development.

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The Membrane Stress Response Buffers Lethal Effects of Lipid Disequilibrium by Reprogramming the Protein Homeostasis Network

Cited by 143 publications

References 59 publications

Yeast phospholipid biosynthesis is linked to mRNA localization

Yeast phospholipid biosynthesis is linked to mRNA localization

The redox requirements of proliferating mammalian cells

The Toxicity of a Novel Antifungal Compound Is Modulated by Endoplasmic Reticulum-Associated Protein Degradation Components

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