The Unfolded Protein Response Is Required for Haploid Tolerance in Yeast

Lee, Kyung-Ho; Neigeborn, Lenore; Kaufman, Randal J.

doi:10.1074/jbc.m210475200

Cited by 21 publications

(6 citation statements)

References 83 publications

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“…While this has been a valuable approach, the risk in comparing gene expression measurements from WT cells and constitutive mutants is that it is difficult to ensure that secondary effects—on gene expression and in the form of genetic suppressors—are not confounding, resulting in misinterpretation of results. Such suppressors have been reported in hac1Δ cells, including in our strain background (Lee et al, 2003). We were concerned that perhaps our identification of non-canonical Hac1 targets might be an unexpected artifact of such secondary effects.…”

Section: Resultssupporting

confidence: 80%

Global Proteome Remodeling during ER Stress Involves Hac1-Driven Expression of Long Undecoded Transcript Isoforms

et al. 2018

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Cellular stress responses often require transcription-based activation of gene expression to promote cellular adaptation. Whether general mechanisms exist for stress-responsive gene downregulation is less clear. A recently defined mechanism enables both up- and downregulation of protein levels for distinct gene sets by the same transcription factor via coordinated induction of canonical mRNAs and long undecoded transcript isoforms (LUTIs). We analyzed parallel gene expression datasets to determine whether this mechanism contributes to the conserved Hac1-driven branch of the unfolded protein response (UPR), indeed observing Hac1-dependent protein downregulation accompanying the upregulation of ER-related proteins that typifies UPR activation. Proteins downregulated by Hac1-driven LUTIs include those with electron transport chain (ETC) function. Abrogated ETC function improves the fitness of UPR-activated cells, suggesting functional importance to this regulation. We conclude that the UPR drives large-scale proteome remodeling, including coordinated up- and downregulation of distinct protein classes, which is partly mediated by Hac1-induced LUTIs.

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Section: Resultssupporting

confidence: 80%

Global Proteome Remodeling during ER Stress Involves Hac1-Driven Expression of Long Undecoded Transcript Isoforms

et al. 2018

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“…Spliced XBP1 functions as a potent transcriptional transactivator of genes involved in ER expansion, protein maturation, folding and export from the ER, as well as export and degradation of misfolded proteins (Yoshida et al, 2001; Calfon et al, 2002; Lee et al, 2002, 2003; Yoshida et al, 2003). ER-bound mRNAs are also degraded in an IRE1 dependent manner via a process called RIDD (“regulated IRE1-dependent decay”) and may serve to limit protein influx and unfolded protein load into the ER lumen after prolonged UPR induction (Hollien and Weissman, 2006; Pirot et al, 2007; Walter and Ron, 2011).…”

Section: The Er Stress Response Signal Is Transduced By 3 Proximal Sementioning

confidence: 99%

The endoplasmic reticulum stress response in aging and age-related diseases

2012

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The endoplasmic reticulum(ER) is a multifunctional organelle within which protein folding, lipid biosynthesis, and calcium storage occurs. Perturbations such as energy or nutrient depletion, disturbances in calcium or redox status that disrupt ER homeostasis lead to the misfolding of proteins, ER stress and up-regulation of several signaling pathways coordinately called the unfolded protein response (UPR). The UPR is characterized by the induction of chaperones, degradation of misfolded proteins and attenuation of protein translation. The UPR plays a fundamental role in the maintenance of cellular homeostasis and thus is central to normal physiology. However, sustained unresolved ER stress leads to apoptosis. Aging linked declines in expression and activity of key ER molecular chaperones and folding enzymes compromise proper protein folding and the adaptive response of the UPR. One mechanism to explain age associated declines in cellular functions and age-related diseases is a progressive failure of chaperoning systems. In many of these diseases, proteins or fragments of proteins convert from their normally soluble forms to insoluble fibrils or plaques that accumulate in a variety of organs including the liver, brain or spleen. This group of diseases, which typically occur late in life includes Alzheimer's, Parkinson's, type II diabetes and a host of less well known but often equally serious conditions such as fatal familial insomnia. The UPR is implicated in many of these neurodegenerative and familial protein folding diseases as well as several cancers and a host of inflammatory diseases including diabetes, atherosclerosis, inflammatory bowel disease and arthritis. This review will discuss age-related changes in the ER stress response and the role of the UPR in age-related diseases.

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“…For example, the UPR will recognize misfolded proteins in the ER lumen using a chaperone protein. The activated UPR turns on an elegant signal transduction pathway that includes splicing of a specific mRNA ( i.e., HAC1 in budding yeast) to promote the production of an active transcription factor and up‐regulation of systems to promote folding and, if prolonged, promote cell death [20,21]. Tunicamycin components are classic activators of the UPR [22].…”

Section: Introductionmentioning

confidence: 99%

tRNA modifications regulate translation during cellular stress

2014

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The regulation of gene expression in response to stress is an essential cellular protection mechanism. Recent advances in tRNA modification analysis and genome-based codon bias analytics have facilitated studies that lead to a novel model for translational control, with translation elongation dynamically regulated during stress responses. Stress-induced increases in specific anticodon wobble bases are required for the optimal translation of stress response transcripts that are significantly biased in the use of degenerate codons keyed to these modified tRNA bases. These findings led us to introduce the notion of tRNA modification tunable transcripts (MoTTs – transcripts whose translation is regulated by tRNA modifications), which are identifiable using genome-wide codon counting algorithms. In support of this general model of translational control of stress response, studies making use of detailed measures of translation, tRNA methyltransferase mutants, and computational and mass spectrometry approaches reveal that stress reprograms tRNA modifications to translationally regulate MoTTs linked to arginine and leucine codons, which helps cells survive insults by damaging agents. These studies highlight how tRNA methyltransferase activities and MoTTs are key components of the cellular stress response.

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The Unfolded Protein Response Is Required for Haploid Tolerance in Yeast

Cited by 21 publications

References 83 publications

Global Proteome Remodeling during ER Stress Involves Hac1-Driven Expression of Long Undecoded Transcript Isoforms

Global Proteome Remodeling during ER Stress Involves Hac1-Driven Expression of Long Undecoded Transcript Isoforms

The endoplasmic reticulum stress response in aging and age-related diseases

tRNA modifications regulate translation during cellular stress

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