Co-chaperone p23 regulates C. elegans Lifespan in Response to Temperature

doi:10.1371/journal.pgen.1005023

. 2015 Apr 1;11(4):e1005023.

doi: 10.1371/journal.pgen.1005023. eCollection 2015 Apr.

Co-chaperone p23 regulates C. elegans Lifespan in Response to Temperature

Makoto Horikawa¹, Surojit Sural², Ao-Lin Hsu³, Adam Antebi⁴

Affiliations

¹ Max Planck Institute for Biology of Ageing, Cologne, Germany.
² University of Michigan, Department of Internal Medicine, Division of Geriatric and Palliative Medicine, Ann Arbor, Michigan, United States of America; University of Michigan, Department of Molecular and Integrative Physiology, Ann Arbor, Michigan, United States of America.
³ University of Michigan, Department of Internal Medicine, Division of Geriatric and Palliative Medicine, Ann Arbor, Michigan, United States of America.
⁴ Max Planck Institute for Biology of Ageing, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Ageing Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Department of Molecular and Cellular Biology, Huffington Center on Ageing, Baylor College of Medicine, Houston, Texas, United States of America.

PMID: 25830239
PMCID: PMC4382338
DOI: 10.1371/journal.pgen.1005023

Co-chaperone p23 regulates C. elegans Lifespan in Response to Temperature

Makoto Horikawa et al. PLoS Genet. 2015.

. 2015 Apr 1;11(4):e1005023.

doi: 10.1371/journal.pgen.1005023. eCollection 2015 Apr.

Authors

Makoto Horikawa¹, Surojit Sural², Ao-Lin Hsu³, Adam Antebi⁴

Affiliations

¹ Max Planck Institute for Biology of Ageing, Cologne, Germany.
² University of Michigan, Department of Internal Medicine, Division of Geriatric and Palliative Medicine, Ann Arbor, Michigan, United States of America; University of Michigan, Department of Molecular and Integrative Physiology, Ann Arbor, Michigan, United States of America.
³ University of Michigan, Department of Internal Medicine, Division of Geriatric and Palliative Medicine, Ann Arbor, Michigan, United States of America.
⁴ Max Planck Institute for Biology of Ageing, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Ageing Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Department of Molecular and Cellular Biology, Huffington Center on Ageing, Baylor College of Medicine, Houston, Texas, United States of America.

PMID: 25830239
PMCID: PMC4382338
DOI: 10.1371/journal.pgen.1005023

Abstract

Temperature potently modulates various physiologic processes including organismal motility, growth rate, reproduction, and ageing. In ectotherms, longevity varies inversely with temperature, with animals living shorter at higher temperatures. Thermal effects on lifespan and other processes are ascribed to passive changes in metabolic rate, but recent evidence also suggests a regulated process. Here, we demonstrate that in response to temperature, daf-41/ZC395.10, the C. elegans homolog of p23 co-chaperone/prostaglandin E synthase-3, governs entry into the long-lived dauer diapause and regulates adult lifespan. daf-41 deletion triggers constitutive entry into the dauer diapause at elevated temperature dependent on neurosensory machinery (daf-10/IFT122), insulin/IGF-1 signaling (daf-16/FOXO), and steroidal signaling (daf-12/FXR). Surprisingly, daf-41 mutation alters the longevity response to temperature, living longer than wild-type at 25°C but shorter than wild-type at 15°C. Longevity phenotypes at 25°C work through daf-16/FOXO and heat shock factor hsf-1, while short lived phenotypes converge on daf-16/FOXO and depend on the daf-12/FXR steroid receptor. Correlatively daf-41 affected expression of DAF-16 and HSF-1 target genes at high temperature, and nuclear extracts from daf-41 animals showed increased occupancy of the heat shock response element. Our studies suggest that daf-41/p23 modulates key transcriptional changes in longevity pathways in response to temperature.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

**Fig 1. *daf-41*/ZC395.10 regulates dauer formation and stress resistance.**
(A) An alignment of protein sequences between C. *elegans* DAF-41, D. *melanogaster* CG16817 and *Homo sapiens* p23/PTGES3. The similarity between DAF-41 and p23/PTGES3 is 44.6%. (B) Schematic illustration of the *daf-41*, and deletion alleles of *ok3015* and *ok3052*. Black arrows indicate the direction of transcription. Red area indicates HSP20-like co-chaperone domain. (C) *daf-41* mutants constitutively formed dauer larvae (Daf-c) weakly at 25°C and strongly at 27°C. (D) Dauer alae of *daf-41(ok3052)* animals grown at 27°C are indicated by the white arrows. (E) *daf-41(ok3052)* worms were resistant for oxidative stress (20mM of H₂O_2, 2.5 hrs) and heat stress (35°C, 8 hrs). *gst-4(ok2358)* worms were also slightly stress tolerant. (F) *daf-41p*::*gfp* (i.e. *dpy-5(e907); sEx10796 [rCes daf-41*::*gfp + pCeh361])* worms were labeled with DiI and photos taken at the young adult stage. Patterns of gene expression of *daf-41p*::*gfp* (green), DiI (red), and merged figures are shown, with arrows indicating individual neurons.

**Fig 2. Genetic interactions of *daf-41* with dauer signaling pathways.**
(A) *daf-41(ok3052)* Daf-c phenotypes were partially suppressed in *af-16(mgDf50)* and completely suppressed in *daf-12(rh61rh411)* backgrounds. (B) *daf-41(ok3052)* Daf-c phenotypes were suppressed in various chemotaxis mutant backgrounds. (C-D) *daf-21(p673)* had no additive effect on Daf-c phenotypes at 25°C, and modestly reduced dauer formation at 27°C in the *daf-41(ok3052)* background. (E) *daf-11(m47)* had no additive effect on dauer formation in the *daf-41(ok3052)* background at 22.5°C. (F) *hsf-1(sy441)* strongly enhanced dauer formation of *daf-41(ok3052)* at 22.5°C. (G) Cultures of *daf-41(ok3052)*, *hsf-1(sy441) and daf-41;hsf-1* are shown grown at 22.5°C. White arrows indicate dauer larvae. All error bars indicate S.D. *, p<0.05; **, p<0.01 versus *daf-41(ok3052);* ††, p<0.01 versus *daf-21(p673)A* or *hsf-1(sy441)* by t-test. (H) *daf-41* regulates dauer formation via *daf-10*, *daf-12* and *daf-16* similar to *daf-21*. However, *hsf-1* suppresses dauer formation in *daf-21* but not *daf-41*. Note that the model reflects genetic interactions, not necessarily direct biochemical interactions.

**Fig 3. *daf-41* mutants extend lifespan at elevated temperatures and shorten life span at lower temperatures.**
(A) *daf-41(ok3052)* mutant animals have a lifespan similar to wild type N2 worms at 20°C (B) *daf-41(ok3052)* animals showed extended lifespan at 25°C (C) *daf-41(ok3052)* animals showed reduced lifespan at 15°C. (D) Lifespan curves of N2 and *daf-41(ok3052)* at different temperatures were plotted onto the same graph as indicated. (E) Mean lifespan of 3 individual experiments were plotted. Error bars, S.D. *, p<0.05; n.s., no significant difference versus N2 by t-test. (F) *daf-41(+)* transgenes rescued Daf-c phenotypes of *daf-41(ok3052)* at 27°C. *dhEx906* and *dhEx907* are independent *daf-41(+)* transgenic lines. *dhEx909* and *dhEx910* are *pges-2(+)* transgenes under control of *daf-41* 5’ and 3’ regulatory elements. Error bars, S.D.; **, p<0.001 versus non-transgenic worms by t-test. (G) Mean lifespan from 3 individual experiments at 15°C, 20°C and 25°C were plotted. Error bars, S.D.; *, p<0.05; **, p<0.01 versus N2; †, p<0.05 versus *daf-41(ok3052);* n.s., no significant difference by t-test. (H) Gene expression of *daf-41* was slightly reduced at 15°C, but no significant differences were measured between 20°C and 25°C. Error bars, S.D. *, p<0.05; n.s., no significance by t-test.

**Fig 4. *daf-41* longevity is dependent on *daf-16*/FOXO.**
(A) *daf-16(mgDf50)* equally reduced the lifespan of *daf-41(ok3052)* and N2 worms at 20°C. (B) *daf-16(mgDf50)* abolished *daf-41* longevity at 25°C. (C) *daf-16(mgDf50)* did not further reduce the short life span of *daf-41(ok3052)* worms at 15°C. (D) Mean lifespan from 3 individual experiments were plotted for the indicated genotypes. Error bars; S.D.; **,p<0.01 versus N2; ††, p<0.01 versus *daf-41(ok3052)* by t-test. (E) DAF-16 target genes, *sod-3*, *dod-3* and *lipl-4*, were significantly upregulated in response to warm temperature in *daf-41(ok3052)* relative to N2. n = 4 biological replicates. Error bars, S.E.M; *, p<0.05 versus N2 of 20°C; †, p<0.05 versus *daf-41(ok3052)* of 20°C by t-test.

**Fig 5. *daf-41(ok3052)* longevity is *hsf-1* dependent.**
(A) *hsf-1(sy441)* shortened both N2 and *daf-41(ok3052)* life span at 20°C. (B) *hsf-1(sy441)* abolished *daf-41(ok3052)* longevity at 25°C. (C) *hsf-1(sy441)* further reduced *daf-41(ok3052)* short life span at 15°C. (D) Mean lifespan from of 3 individual experiments were plotted for indicated genotypes and conditions. Error bars, S.D.; *, p<0.05; **, p<0.01 versus N2; †, p<0.05; ††, p<0.01 versus *daf-41(ok3052)* by t-test. (E) *daf-41(ok3052)* enhanced the upregulation of HSF-1 target genes, *hsp-16*.2, *hsp-4*, and *hsp-70*, in response to warm temperature. n = 4 biological replicates. Error bars, S.E.M; *, p<0.05 versus N2 of 20°C; †, p<0.05 versus *daf-41(ok3052)* of 20°C by t-test. (F) HSF-1 binding activity to HSE was 1.5 fold increased in *daf-41(ok3052)* at 25°C. Error bars, S.E.M; **, p<0.01 versus N2. (G) At 15°C, *daf-21(p673)* mutation enhanced the longevity of N2 and *daf-41(ok3052)*. At 20°C, *daf-21* mutant animals lived slightly longer than N2. At 25°C, *daf-21(p673)* animals lived slightly longer than WT but the mutation reduced longevity in the *daf-41(ok3052)* background.

**Fig 6. The short life span of *daf-41(ok3052)* at 15°C is *daf-12* dependent.**
(A-B) *daf-12(rh61rh411)* reduced longevity of *daf-41(ok3052)* at 20°C and 25°C. (C) *daf-12(rh61rh411)* partly rescued the short life span of *daf-41(ok3052)* at 15°C. (D) Mean lifespan from 3 individual experiments are plotted with indicated genotypes and conditions. Error bars, S.D.; *, p<0.05; **, p<0.01 versus N2; †, p<0.05; ††, p<0.01 versus *daf-41(ok3052)* by t-test. (E) Transcriptional targets of DAF-12, *cdr-6* and *fard-1*, were reduced with temperature in N2, but this tendency was reversed in the *daf-41(ok3052)* background. n = 4 biological replicates. Error bars, S.E.M; *, p<0.05 versus N2 of 20°C; †, p<0.05 versus *daf-41(ok3052)* of 20°C by t-test.

**Fig 7. *daf-41* partially interacts with the chemosensory and thermosensory apparatus to regulate longevity.**
(A) Mean lifespan of 3 individual experiments were plotted. The triple mutant of *gcy-23(nj37) gcy-8(oy44) gcy-18(nj38) (gcy* triple) caused a parallel reduction of lifespan in N2 and *daf-41(ok3052)*, respectively at 25°C. The *gcy* triple mutant did not further shorten the life span of daf-41(ok3052) at 15°C. (B) *daf-10* mutation increased lifespan in parallel to *daf-41* at 15°C and 20°C. *daf-10* mutation did not further extend the life span of *daf-41(ok3052)* worms at 25°C. Error bars, S.D.; *, p<0.05; **, p<0.01 versus N2; †, p<0.05; ††, p<0.01 versus *daf-41(ok3052)* by t-test. (C) A schematic model describing the regulatory mechanism of longevity by *daf-41* at different temperatures. At 25°C, *daf-41* negatively regulates the transcriptional activities of DAF-16 and HSF-1 and their down-regulation results in normal life span. Thermotaxis and steroidal signaling may regulate longevity in parallel to *daf-41*. At 15°C, *daf-41* (+) contributes to longevity possibly via *daf-16/*FOXO. *daf-41(+)* may also prevent life shortening activities of *daf-12(+)*, while *hsf-1* may promote longevity in parallel. These are working models that we interpret with caution, and may reflect direct or indirect interactions.

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References

1. Miquel J, Lundgren PR, Bensch KG, Atlan H (1976) Effects of temperature on the life span, vitality and fine structure of Drosophila melanogaster. Mech Ageing Dev 5: 347–370. - PubMed
1. Klass MR (1977) Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech Ageing Dev 6: 413–429. - PubMed
1. Lee WS, Monaghan P, Metcalfe NB (2013) Experimental demonstration of the growth rate—lifespan trade-off. Proc Biol Sci 280: 20122370 10.1098/rspb.2012.2370 - DOI - PMC - PubMed
1. Lee SJ, Kenyon C (2009) Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans. Curr Biol 19: 715–722. 10.1016/j.cub.2009.03.041 - DOI - PMC - PubMed
1. Xiao R, Zhang B, Dong Y, Gong J, Xu T, et al. (2013) A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel. Cell 152: 806–817. 10.1016/j.cell.2013.01.020 - DOI - PMC - PubMed

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[1] Miquel J, Lundgren PR, Bensch KG, Atlan H (1976) Effects of temperature on the life span, vitality and fine structure of Drosophila melanogaster. Mech Ageing Dev 5: 347–370. - PubMed

[2] Miquel J, Lundgren PR, Bensch KG, Atlan H (1976) Effects of temperature on the life span, vitality and fine structure of Drosophila melanogaster. Mech Ageing Dev 5: 347–370. - PubMed

[3] Klass MR (1977) Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech Ageing Dev 6: 413–429. - PubMed

[4] Klass MR (1977) Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech Ageing Dev 6: 413–429. - PubMed

[5] Lee WS, Monaghan P, Metcalfe NB (2013) Experimental demonstration of the growth rate—lifespan trade-off. Proc Biol Sci 280: 20122370 10.1098/rspb.2012.2370 - DOI - PMC - PubMed

[6] Lee WS, Monaghan P, Metcalfe NB (2013) Experimental demonstration of the growth rate—lifespan trade-off. Proc Biol Sci 280: 20122370 10.1098/rspb.2012.2370 - DOI - PMC - PubMed

[7] Lee SJ, Kenyon C (2009) Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans. Curr Biol 19: 715–722. 10.1016/j.cub.2009.03.041 - DOI - PMC - PubMed

[8] Lee SJ, Kenyon C (2009) Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans. Curr Biol 19: 715–722. 10.1016/j.cub.2009.03.041 - DOI - PMC - PubMed

[9] Xiao R, Zhang B, Dong Y, Gong J, Xu T, et al. (2013) A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel. Cell 152: 806–817. 10.1016/j.cell.2013.01.020 - DOI - PMC - PubMed

[10] Xiao R, Zhang B, Dong Y, Gong J, Xu T, et al. (2013) A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel. Cell 152: 806–817. 10.1016/j.cell.2013.01.020 - DOI - PMC - PubMed

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Co-chaperone p23 regulates C. elegans Lifespan in Response to Temperature

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Co-chaperone p23 regulates C. elegans Lifespan in Response to Temperature

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