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PMID:24068940

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Citation

Glover-Cutter, KM, Lin, S and Blackwell, TK (2013) Integration of the unfolded protein and oxidative stress responses through SKN-1/Nrf. PLoS Genet. 9:e1003701

Abstract

The Unfolded Protein Response (UPR) maintains homeostasis in the endoplasmic reticulum (ER) and defends against ER stress, an underlying factor in various human diseases. During the UPR, numerous genes are activated that sustain and protect the ER. These responses are known to involve the canonical UPR transcription factors XBP1, ATF4, and ATF6. Here, we show in C. elegans that the conserved stress defense factor SKN-1/Nrf plays a central and essential role in the transcriptional UPR. While SKN-1/Nrf has a well-established function in protection against oxidative and xenobiotic stress, we find that it also mobilizes an overlapping but distinct response to ER stress. SKN-1/Nrf is regulated by the UPR, directly controls UPR signaling and transcription factor genes, binds to common downstream targets with XBP-1 and ATF-6, and is present at the ER. SKN-1/Nrf is also essential for resistance to ER stress, including reductive stress. Remarkably, SKN-1/Nrf-mediated responses to oxidative stress depend upon signaling from the ER. We conclude that SKN-1/Nrf plays a critical role in the UPR, but orchestrates a distinct oxidative stress response that is licensed by ER signaling. Regulatory integration through SKN-1/Nrf may coordinate ER and cytoplasmic homeostasis.

Links

PubMed PMC3772064 Online version:10.1371/journal.pgen.1003701

Keywords

Animals; Caenorhabditis elegans/genetics; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins/genetics; Cytoplasm/genetics; DNA-Binding Proteins/genetics; Endoplasmic Reticulum/genetics; Endoplasmic Reticulum/metabolism; Endoplasmic Reticulum Stress/genetics; Humans; Oxidative Stress/genetics; Signal Transduction; Transcription Factors/genetics; Transcription, Genetic; Unfolded Protein Response/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:BIBH

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P34707

F

Seeded From UniProt

complete

CAEEL:SKN1

located_in

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:SKN1

enables

GO:0000977: RNA polymerase II transcription regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • part_of:(GO:0030968)
  • has_input:(WB:WBGene00004804)

Seeded From UniProt

complete

CAEEL:Q20435

enables

GO:0000977: RNA polymerase II transcription regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • part_of:(GO:0030968)
  • has_input:(WB:WBGene00004804)

Seeded From UniProt

complete

CAEEL:SKN1

involved_in

GO:0006990: positive regulation of transcription from RNA polymerase II promoter involved in unfolded protein response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:SKN1

part_of

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:SKN1

enables

GO:0000977: RNA polymerase II regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • happens_during:(GO:0030968)
  • has_direct_input:(WB:WBGene00004804)

Seeded From UniProt

complete

CAEEL:SKN1

enables

GO:0030544: Hsp70 protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P20163

F

Seeded From UniProt

complete

Notes

See also

References

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