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Genetic Interactions Due to Constitutive and Inducible Gene Regulation Mediated by the Unfolded Protein Response in C. elegans

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      The unfolded protein response (UPR) is an adaptive signaling pathway utilized to sense and alleviate the stress of protein folding in the endoplasmic reticulum (ER). In mammals, the UPR is mediated through three proximal sensors PERK/PEK, IRE1, and ATF6. PERK/PEK is a protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 to inhibit protein synthesis. Activation of IRE1 induces splicing of XBP1 mRNA to produce a potent transcription factor. ATF6 is a transmembrane transcription factor that is activated by cleavage upon ER stress. We show that in Caenorhabditis elegans, deletion of either ire-1 or xbp-1 is synthetically lethal with deletion of either atf-6 or pek-1, both producing a developmental arrest at larval stage 2. Therefore, in C. elegans, atf-6 acts synergistically with pek-1 to complement the developmental requirement for ire-1 and xbp-1. Microarray analysis identified inducible UPR (i-UPR) genes, as well as numerous constitutive UPR (c-UPR) genes that require the ER stress transducers during normal development. Although ire-1 and xbp-1 together regulate transcription of most i-UPR genes, they are each required for expression of nonoverlapping sets of c-UPR genes, suggesting that they have distinct functions. Intriguingly, C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis. In contrast, pek-1 is required for induction of approximately 23% of i-UPR genes but is dispensable for the c-UPR. As pek-1 and atf-6 mainly act through sets of nonoverlapping targets that are different from ire-1 and xbp-1 targets, at least two coordinated responses are required to alleviate ER stress by distinct mechanisms. Finally, our array study identified the liver-specific transcription factor CREBh as a novel UPR gene conserved during metazoan evolution.



      The endoplasmic reticulum (ER) is an intracellular organelle where proteins fold and assemble prior to transport to the cell surface. The ER contains a finely tuned quality control apparatus to ensure that improperly folded proteins are retained in the ER lumen. A variety of physiological demands, environmental perturbations, and pathological conditions compromise protein folding in the ER and lead to the accumulation of unfolded proteins. The unfolded protein response (UPR) is an evolutionarily conserved intracellular adaptive signaling pathway that alleviates protein-folding defects in the ER. The unfolded protein signal is transmitted from the ER to the nucleus by three pathways involving the proteins ATF-6, PEK-1, and IRE-1/XBP-1. However, it is not known how these three pathways coordinate downstream transcriptional activation to mediate either cell adaptation or cell death. The authors have studied the nematode Caenorhabditis elegans to present a comprehensive genetic and gene expression analysis of the three UPR pathways. The findings demonstrate that the UPR regulates the expression of hundreds of genes in the presence, as well as the absence, of ER stress in a manner that is more complex and diverse than previously known.

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      Most cited references 66

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      Methods are described for the isolation, complementation and mapping of mutants of Caenorhabditis elegans, a small free-living nematode worm. About 300 EMS-induced mutants affecting behavior and morphology have been characterized and about one hundred genes have been defined. Mutations in 77 of these alter the movement of the animal. Estimates of the induced mutation frequency of both the visible mutants and X chromosome lethals suggests that, just as in Drosophila, the genetic units in C. elegans are large.
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        Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans.

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        Experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene. Such effects have been proposed to result from a simple antisense mechanism that depends on hybridization between the injected RNA and endogenous messenger RNA transcripts. RNA interference has been used in the nematode Caenorhabditis elegans to manipulate gene expression. Here we investigate the requirements for structure and delivery of the interfering RNA. To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually. After injection into adult animals, purified single strands had at most a modest effect, whereas double-stranded mixtures caused potent and specific interference. The effects of this interference were evident in both the injected animals and their progeny. Only a few molecules of injected double-stranded RNA were required per affected cell, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process.
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          An integrated stress response regulates amino acid metabolism and resistance to oxidative stress.

          Eukaryotic cells respond to unfolded proteins in their endoplasmic reticulum (ER stress), amino acid starvation, or oxidants by phosphorylating the alpha subunit of translation initiation factor 2 (eIF2alpha). This adaptation inhibits general protein synthesis while promoting translation and expression of the transcription factor ATF4. Atf4(-/-) cells are impaired in expressing genes involved in amino acid import, glutathione biosynthesis, and resistance to oxidative stress. Perk(-/-) cells, lacking an upstream ER stress-activated eIF2alpha kinase that activates Atf4, accumulate endogenous peroxides during ER stress, whereas interference with the ER oxidase ERO1 abrogates such accumulation. A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.

            Author and article information

            [1 ] Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
            [2 ] Department of Molecular Biology, The UMDNJ School of Osteopathic Medicine, Stratford, New Jersey, United States of America
            Stanford University School of Medicine, United States of America
            Author notes
            *To whom correspondence should be addressed. E-mail: kaufmanr@

            ¤ Current address: Children's Hospital, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America

            Role: Editor
            PLoS Genet
            PLoS Genetics
            September 2005
            23 September 2005
            : 1
            : 3
            05-PLGE-RA-0082R2 plge-01-03-09
            Copyright: © 2005 Shen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Research Article
            Cell Biology
            Molecular Biology - Structural Biology
            Genetics/Gene Function
            Genetics/Gene Expression
            Custom metadata
            Shen X, Ellis RE, Sakaki K, Kaufman RJ (2005) Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans. PLoS Genet 1(3): e37.



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