ER stress-unfolded protein response (UPRer) (WP2578)

Caenorhabditis elegans

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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.

Authors

Karen Yook , Christian Grove , Alex Pico , Eric Weitz , Stefan Raats , and Egon Willighagen

Activity

last edited

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Cited In

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Organisms

Caenorhabditis elegans

Communities

WormBase

Annotations

Pathway Ontology

endoplasmic reticulum stress - the unfolded protein response pathway

Participants

Label Type Compact URI Comment
tunicamycin Metabolite chebi:29699
uggt-1 GeneProduct wormbase:F48E3.3
ATF-6 bZip domain GeneProduct wormbase:F45E6.2 UPR transducer. Few genes depend on ATF-6 induction in response to ER-stress.
PEK-1 GeneProduct wormbase:F46C3.1 UPR-transducer
apy-1 GeneProduct wormbase:F08C6.6
hsp-4 GeneProduct wormbase:F43E2.8
crt-1 GeneProduct wormbase:Y38A10A.5
eIF2alpha GeneProduct ensembl:WBGene00021351
S2PProtease GeneProduct ensembl:WBGene00013225
cht-1 GeneProduct wormbase:C04F6.3
xbp-1 mRNA GeneProduct wormbase:R74.3
CRT-1 GeneProduct wormbase:Y38A10A.5
ABU-1 GeneProduct wormbase:AC3.3
HSP-3/ BiP/GRP78 GeneProduct wormbase:C15H9.6
APY-1 GeneProduct wormbase:F08C6.6
HSP-4/ BiP/GRP78 GeneProduct wormbase:F43E2.8
HUT-1 GeneProduct wormbase:Y111B2A.20 HUT-1 is a UDP-Galactose transporter required for normal ER homeostasis
IRE-1 GeneProduct wormbase:C41C4.4 UPR transducer
eIF2alpha GeneProduct ensembl:WBGene00021351
XBP-1 GeneProduct wormbase:R74.3
ATF-6 GeneProduct wormbase:F45E6.2 UPR transducer. Few genes depend on ATF-6 induction in response to ER-stress.
HSP-3/ BiP/GRP78 GeneProduct wormbase:C15H9.6
CRT-1 GeneProduct wormbase:Y38A10A.5
APY-1 GeneProduct wormbase:F08C6.6
uggt-2 GeneProduct wormbase:F26H9.8
PEK-1 GeneProduct wormbase:F46C3.1 UPR-transducer
PEK-1 GeneProduct wormbase:F46C3.1 UPR-transducer
IRE-1 GeneProduct wormbase:C41C4.4 UPR transducer
IRE-1 GeneProduct wormbase:C41C4.4 UPR transducer
ATF-6 GeneProduct wormbase:F45E6.2 UPR transducer. Few genes depend on ATF-6 induction in response to ER-stress.
ATF-6 GeneProduct wormbase:F45E6.2 UPR transducer. Few genes depend on ATF-6 induction in response to ER-stress.
IRE-1 GeneProduct wormbase:C41C4.4 UPR transducer
IRE-1 GeneProduct wormbase:C41C4.4 UPR transducer
UGGT-1 Protein wormbase:F48E3.3
HSP-4/ BiP/GRP78 Protein wormbase:F43E2.8
UGGT-1 Protein wormbase:F48E3.3
UGGT-2 Protein wormbase:F26H9.8
UGGT-2 Protein wormbase:F26H9.8

References

  1. 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. Sood R, Porter AC, Ma K, Quilliam LA, Wek RC. Biochem J. 2000 Mar 1;346 Pt 2(Pt 2):281–93. PubMed Europe PMC Scholia
  2. Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Shen X, Ellis RE, Lee K, Liu CY, Yang K, Solomon A, et al. Cell. 2001 Dec 28;107(7):893–903. PubMed Europe PMC Scholia
  3. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, et al. Nature. 2002 Jan 3;415(6867):92–6. PubMed Europe PMC Scholia
  4. A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response. Urano F, Calfon M, Yoneda T, Yun C, Kiraly M, Clark SG, et al. J Cell Biol. 2002 Aug 19;158(4):639–46. PubMed Europe PMC Scholia
  5. Compensatory regulation among ER chaperones in C. elegans. Kapulkin WJ, Hiester BG, Link CD. FEBS Lett. 2005 Jun 6;579(14):3063–8. PubMed Europe PMC Scholia
  6. Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans. Shen X, Ellis RE, Sakaki K, Kaufman RJ. PLoS Genet. 2005 Sep;1(3):e37. PubMed Europe PMC Scholia
  7. Differential requirement of unfolded protein response pathway for calreticulin expression in Caenorhabditis elegans. Lee D, Singaravelu G, Park BJ, Ahnn J. J Mol Biol. 2007 Sep 14;372(2):331–40. PubMed Europe PMC Scholia
  8. APY-1, a novel Caenorhabditis elegans apyrase involved in unfolded protein response signalling and stress responses. Uccelletti D, Pascoli A, Farina F, Alberti A, Mancini P, Hirschberg CB, et al. Mol Biol Cell. 2008 Apr;19(4):1337–45. PubMed Europe PMC Scholia
  9. 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. Dejima K, Murata D, Mizuguchi S, Nomura KH, Gengyo-Ando K, Mitani S, et al. FASEB J. 2009 Jul;23(7):2215–25. PubMed Europe PMC Scholia
  10. Signalling pathways in the unfolded protein response: development from yeast to mammals. Mori K. J Biochem. 2009 Dec;146(6):743–50. PubMed Europe PMC Scholia
  11. The two Caenorhabditis elegans UDP-glucose:glycoprotein glucosyltransferase homologues have distinct biological functions. Buzzi LI, Simonetta SH, Parodi AJ, Castro OA. PLoS One. 2011;6(11):e27025. PubMed Europe PMC Scholia