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PMID:25330323

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Citation

Warnhoff, K, Murphy, JT, Kumar, S, Schneider, DL, Peterson, M, Hsu, S, Guthrie, J, Robertson, JD and Kornfeld, K (2014) The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation. PLoS Genet. 10:e1004703

Abstract

The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance.

Links

PubMed PMC4199503 Online version:10.1371/journal.pgen.1004703

Keywords


Significance

Annotations

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

CAEEL:O16486

involved_in

GO:0017196: N-terminal peptidyl-methionine acetylation

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q147X3

P

Seeded From UniProt

complete

CAEEL:O16486

enables

GO:0004596: peptide alpha-N-acetyltransferase activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q147X3

F

Seeded From UniProt

complete

CAEEL:O16486

part_of

GO:0031417: NatC complex

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q147X3

C

Seeded From UniProt

complete

CAEEL:O16486

involved_in

GO:0040024: dauer larval development

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:FOXO

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(WB:WBGene00020719)

Seeded From UniProt

complete

CAEEL:O17003

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:0009408: response to heat

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:0009408: response to heat

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000912

P

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:0009408: response to heat

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:0006474: N-terminal protein amino acid acetylation

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q02197

P

Seeded From UniProt

complete

CAEEL:O17003

contributes_to

GO:0004596: peptide alpha-N-acetyltransferase activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q02197

F

Seeded From UniProt

complete

CAEEL:O17003

part_of

GO:0031417: NatC complex

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q5VZE5

C

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:1990359: stress response to zinc ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:1990359: stress response to zinc ion

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000912

P

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:1990359: stress response to zinc ion

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00009813

P

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:1990170: stress response to cadmium ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:1990169: stress response to copper ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:1901562: response to paraquat

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:O17003

involved_in

GO:0040024: dauer larval development

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:HUTH1

involved_in

GO:1990359: stress response to zinc ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:HUTH1

involved_in

GO:1990359: stress response to zinc ion

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00020719

P

Seeded From UniProt

complete

CAEEL:FOXO

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_regulation_target:(WB:WBGene00020719)

Seeded From UniProt

complete

Notes

See also

References

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