ER Stress-Unfolded Protein Response (UPRer) (Caenorhabditis elegans)

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Endoplasmic Reticulum2, 5, 7, 10271121111831134Golgi ApparatusNucleus.......ER ChaperonesUnfolded ProteinsLEGENDDirect or indirect stimulationEnvironmental stress (e.g. heat, hypoxia, pathogens)Translocation, change of state, translation139 genes induced by IRE-1/XBP-1 pathwayuggt-1ATF-6 bZip domain5, 7TranslationPEK-17, 10UGGT-1apy-1hsp-4crt-1eIF2alphaS2PProteasecht-1xbp-1 mRNAtunicamycinBiP/ GRP78CRT-1Development10ERAD PathwayABU-1HSP-3/ BiP/GRP78APY-1HSP-4/ BiP/GRP78HUT-1IRE-177, 921 genes induced by PEK-1eIF2alphaXBP-11mRNA splicingER Stress (unfolded proteins)7, 9Activates a processProteolytic cleavageATF-65, 7ER homeostasis10HSP-4/ BiP/GRP78HSP-3/ BiP/GRP78CRT-1APY-1uggt-2UGGT-1UGGT-2UGGT-2UDP EnzymesUDP EnzymesER ChaperonesPEK-1BiP/ GRP787, 10PEK-17, 10IRE-17IRE-17ATF-65, 7ATF-65, 7P5CatalysisGene TranscriptionDirect or indirect inhibition10BiP/ GRP78IRE-1IRE-177


Description

Correctly folding proteins is a severely complicated process that fails at times, despite the controlled environment of the ER and numerous molecular helpers. Under normal conditions, these misfolded proteins are degraded through the ER-associated degradation (ERAD) mechanism. However, various physiological or environmental stressors can inhibit or overwhelm these normal mechanisms resulting in an increase in the amount of misfolded proteins, which trigger the Unfolded Protein Response (UPR). Organisms have evolved the UPR to handle this ER stress and suppress the toxicity of accumulated misfolded proteins (proteotoxicity). In mammals the UPR attenuates protein synthesis through PERK/PEK1 and increases transcription of folding and ERAD components through activation of potent transcription factors through IRE1 splicing of XBP1 mRNA and ER-stress cleavage of ATF-6. These events ultimately augment folding and enhance degradation capacity of the organelle. In C. elegans, the UPR also activates transcriptional regulators that reduce protein synthesis and increase the number of components necessary to deal with misfolded proteins.

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Bibliography

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  1. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D; ''IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA.''; Nature, 2002 PubMed Europe PMC
  2. Urano F, Calfon M, Yoneda T, Yun C, Kiraly M, Clark SG, Ron D; ''A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response.''; J Cell Biol, 2002 PubMed Europe PMC
  3. Buzzi LI, Simonetta SH, Parodi AJ, Castro OA; ''The two Caenorhabditis elegans UDP-glucose:glycoprotein glucosyltransferase homologues have distinct biological functions.''; PLoS One, 2011 PubMed Europe PMC
  4. Kapulkin WJ, Hiester BG, Link CD; ''Compensatory regulation among ER chaperones in C. elegans.''; FEBS Lett, 2005 PubMed Europe PMC
  5. Shen X, Ellis RE, Sakaki K, Kaufman RJ; ''Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans.''; PLoS Genet, 2005 PubMed Europe PMC
  6. Greenwald I, Kovall R; ''Notch signaling: genetics and structure.''; WormBook, 2013 PubMed Europe PMC
  7. Mori K; ''Signalling pathways in the unfolded protein response: development from yeast to mammals.''; J Biochem, 2009 PubMed Europe PMC
  8. Dejima K, Murata D, Mizuguchi S, Nomura KH, Gengyo-Ando K, Mitani S, Kamiyama S, Nishihara S, Nomura K; ''The ortholog of human solute carrier family 35 member B1 (UDP-galactose transporter-related protein 1)is involved in maintenance of ER homeostasis and essential for larval development in Caenorhabditis elegans.''; FASEB J, 2009 PubMed Europe PMC
  9. Sood R, Porter AC, Ma K, Quilliam LA, Wek RC; ''Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress.''; Biochem J, 2000 PubMed Europe PMC
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  11. Uccelletti D, Pascoli A, Farina F, Alberti A, Mancini P, Hirschberg CB, Palleschi C; ''APY-1, a novel Caenorhabditis elegans apyrase involved in unfolded protein response signalling and stress responses.''; Mol Biol Cell, 2008 PubMed Europe PMC
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History

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CompareRevisionActionTimeUserComment
84474view19:34, 25 February 2016AlexanderPicoQuick edit to datanode annotation or property
84473view19:33, 25 February 2016AlexanderPicoQuick edit to datanode annotation or property
78452view10:27, 7 January 2015MaintBotadded missing graphIds
77651view20:45, 1 October 2014Kyookremoved distracting red color from UPR trigger
74854view23:23, 1 May 2014CgroveCleaning up
74853view23:21, 1 May 2014CgroveCleaning up
74410view18:13, 16 April 2014CgroveAdded IRE-1 oligomers and IRE-1 directly binding to unfolded protein
73888view22:28, 28 February 2014CgroveCleaning up
73887view22:20, 28 February 2014CgroveAdded ERAD WikiPathway link
73449view21:59, 29 January 2014CgroveCleaning up
73448view21:57, 29 January 2014CgroveCleaning up legend
73447view21:50, 29 January 2014CgrovePeriodical save, work in progress
73446view21:49, 29 January 2014CgroveCleaning up
73445view21:45, 29 January 2014CgroveCleaning up, adding legend
73444view21:40, 29 January 2014CgrovePeriodical save, work in progress
73443view21:30, 29 January 2014CgrovePeriodical save, work in progress
73356view23:31, 22 January 2014CgroveCleaning up
73355view23:30, 22 January 2014CgroveCleaning up
73354view23:26, 22 January 2014CgroveCleaning up
73353view23:24, 22 January 2014CgrovePeriodical save, work in progress
73352view23:16, 22 January 2014CgroveAdded BiP/GRP78 to monomeric IRE-1 and PEK-1 in the ER lumen
73351view23:14, 22 January 2014CgrovePeriodical save, work in progress
73350view23:00, 22 January 2014CgroveAdded "S2P Protease" to Y56A3A.2 node
73349view22:59, 22 January 2014CgroveCleaning up
73348view22:56, 22 January 2014CgroveCleaning up
73296view00:06, 15 January 2014CgroveCleaning up
73295view00:04, 15 January 2014CgrovePeriodical save, work in progress
73294view00:02, 15 January 2014CgroveCleaning up
73293view23:54, 14 January 2014CgrovePeriodical save, work in progress
73292view23:46, 14 January 2014CgroveCleaning up
73291view23:44, 14 January 2014CgrovePeriodical save, work in progress
73290view23:38, 14 January 2014CgroveCleaning up
73289view23:34, 14 January 2014CgrovePeriodical save, work in progress
73266view00:28, 14 January 2014CgroveAdded reference for S2P (Y56A3A.2) cleavage of ATF-6
73263view23:28, 13 January 2014Cgrovecleaning up
73262view23:23, 13 January 2014CgroveY56A3A.2 protease catalyzing cleavage of ATF-6 protein
73261view23:11, 13 January 2014CgroveCleaning up; Added IRE-1 and PEK-1 dimerization
73260view23:05, 13 January 2014CgrovePeriodical save, work in progress
73249view21:04, 13 January 2014CgroveAdded pathogens to list of environmental stressors
73248view21:01, 13 January 2014CgroveAdded "UDP Enzymes" label and another "ER Chaperones" label
73247view20:58, 13 January 2014CgroveAdded UGGT-1 and UGGT-2 enzymes, regulated by IRE-1 branch of the UPR pathway
73246view20:56, 13 January 2014CgrovePeriodical save, work in progress
73245view20:37, 13 January 2014CgroveAdded examples of environmental stress including heat and hypoxia
73208view23:05, 10 January 2014CgroveAdded reference for HUT-1
73207view23:04, 10 January 2014CgroveAdded HUT-1 UDP-galactose transporter
73206view22:43, 10 January 2014CgroveCleaning up
73205view22:41, 10 January 2014CgroveAdded APY-1 UDP/GDPase glycosylation enzyme affect on ER UPR
73204view22:35, 10 January 2014CgrovePeriodical save, work in progress
73203view22:23, 10 January 2014CgroveCleaning up
73202view22:23, 10 January 2014CgroveAdded Calreticulin (CRT-1) chaperone and HSP-3 chaperone, and translocation of chaperones to ER lumen

External references

DataNodes

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NameTypeDatabase referenceComment
ABU-1GeneProductAC3.3 (WormBase)
APY-1GeneProductF08C6.6 (WormBase)
ATF-6 bZip domainGeneProductF45E6.2 (WormBase) UPR transducer. Few genes depend on ATF-6 induction in response to ER-stress.
ATF-6GeneProductF45E6.2 (WormBase) UPR transducer. Few genes depend on ATF-6 induction in response to ER-stress.
BiP/ GRP78ProteinAlthough not directly shown in C. elegans, BiP/GRP78 (HSP-3 or HSP-4 in C. elegans) has been shown to bind to IRE-1 in its monomeric state in other organisms. Unfolded proteins are thought to compete with IRE-1 for binding to BiP/GRP78 such that an increased load of unfolded proteins would cause dissociation of BiP/GRP78 from IRE-1, thereby allowing IRE-1 dimerization and subsequent activation of XBP-1.
CRT-1GeneProductY38A10A.5 (WormBase)
DevelopmentPathway
ER homeostasisPathway
ERAD PathwayPathwayWP2591 (WikiPathways)
HSP-3/ BiP/GRP78GeneProductC15H9.6 (WormBase)
HSP-4/ BiP/GRP78ProteinF43E2.8 (WormBase)
HUT-1GeneProductY111B2A.20 (WormBase) HUT-1 is a UDP-Galactose transporter required for normal ER homeostasis
IRE-1GeneProductC41C4.4 (WormBase) UPR transducer
PEK-1GeneProductF46C3.1 (WormBase) UPR-transducer
S2PProteaseGeneProductWBGene00013225 (Ensembl)
TranslationPathway
UGGT-1ProteinF48E3.3 (WormBase)
UGGT-2ProteinF26H9.8 (WormBase)
XBP-1GeneProductR74.3 (WormBase)
apy-1GeneProductF08C6.6 (WormBase)
cht-1GeneProductC04F6.3 (WormBase)
crt-1GeneProductY38A10A.5 (WormBase)
eIF2alphaGeneProductWBGene00021351 (Ensembl)
hsp-4GeneProductF43E2.8 (WormBase)
tunicamycinMetaboliteCHEBI:29699 (ChEBI)
uggt-1GeneProductF48E3.3 (WormBase)
uggt-2GeneProductF26H9.8 (WormBase)
xbp-1 mRNAGeneProductR74.3 (WormBase)

Annotated Interactions

No annotated interactions

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