The heat shock response (HSR) is essential to survive acute proteotoxic stress and has been studied extensively in unicellular organisms and tissue culture cells, but to a lesser extent in intact metazoan animals. To identify the regulatory pathways that control the HSR in Caenorhabditis elegans, we performed a genome-wide RNAi screen and identified 59 genes corresponding to 7 positive activators required for the HSR and 52 negative regulators whose knockdown leads to constitutive activation of the HSR. These modifiers function in specific steps of gene expression, protein synthesis, protein folding, trafficking, and protein clearance, and comprise the metazoan heat shock regulatory network (HSN). Whereas the positive regulators function in all tissues of C. elegans, nearly all of the negative regulators exhibited tissue-selective effects. Knockdown of the subunits of the proteasome strongly induces HS reporter expression only in the intestine and spermatheca but not in muscle cells, while knockdown of subunits of the TRiC/CCT chaperonin induces HS reporter expression only in muscle cells. Yet, both the proteasome and TRiC/CCT chaperonin are ubiquitously expressed and are required for clearance and folding in all tissues. We propose that the HSN identifies a key subset of the proteostasis machinery that regulates the HSR according to the unique functional requirements of each tissue.
Vyšlo v časopise: Identification of a Tissue-Selective Heat Shock Response Regulatory Network. PLoS Genet 9(4): e32767. doi:10.1371/journal.pgen.1003466 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003466
1. AkerfeltM, MorimotoRI, SistonenL (2010) Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 8 : 545–555.
2. CraigEA, GrossCA (1991) Is hsp70 the cellular thermometer? Trends Biochem Sci 16 : 135–140.
3. AbravayaK, MyersMP, MurphySP, MorimotoRI (1992) The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression. Genes Dev 6 : 1153–1164.
4. BalerR, WelchWJ, VoellmyR (1992) Heat shock gene regulation by nascent polypeptides and denatured proteins: hsp70 as a potential autoregulatory factor. J Cell Biol 117 : 1151–1159.
5. MosserDD, DuchaineJ, MassieB (1993) The DNA-binding activity of the human heat shock transcription factor is regulated in vivo by hsp70. Mol Cell Biol 13 : 5427–5438.
6. ShiY, MosserDD, MorimotoRI (1998) Molecular chaperones as HSF1-specific transcriptional repressors. Genes Dev 12 : 654–666.
7. ZouJ, GuoY, GuettoucheT, SmithDF, VoellmyR (1998) Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94 : 471–480.
8. ElefantF, PalterKB (1999) Tissue-specific expression of dominant negative mutant Drosophila HSC70 causes developmental defects and lethality. Mol Biol Cell 10 : 2101–2117.
9. MathurSK, SistonenL, BrownIR, MurphySP, SargeKD, et al. (1994) Deficient induction of human hsp70 heat shock gene transcription in Y79 retinoblastoma cells despite activation of heat shock factor 1. Proc Natl Acad Sci U S A 91 : 8695–8699.
10. MarcuccilliCJ, MathurSK, MorimotoRI, MillerRJ (1996) Regulatory differences in the stress response of hippocampal neurons and glial cells after heat shock. J Neurosci 16 : 478–485.
11. BatulanZ, ShinderGA, MinottiS, HeBP, DoroudchiMM, et al. (2003) High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. J Neurosci 23 : 5789–5798.
12. BlakeMJ, GershonD, FargnoliJ, HolbrookNJ (1990) Discordant expression of heat shock protein mRNAs in tissues of heat-stressed rats. J Biol Chem 265 : 15275–15279.
13. MorleyJF, MorimotoRI (2004) Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 15 : 657–664.
14. WuBJ, WilliamsGT, MorimotoRI (1987) Detection of three protein binding sites in the serum-regulated promoter of the human gene encoding the 70-kDa heat shock protein. Proc Natl Acad Sci U S A 84 : 2203–2207.
15. WilliamsGT, McClanahanTK, MorimotoRI (1989) E1a transactivation of the human HSP70 promoter is mediated through the basal transcriptional complex. Mol Cell Biol 9 : 2574–2587.
16. MorganWD, WilliamsGT, MorimotoRI, GreeneJ, KingstonRE, et al. (1987) Two transcriptional activators, CCAAT-box-binding transcription factor and heat shock transcription factor, interact with a human hsp70 gene promoter. Mol Cell Biol 7 : 1129–1138.
17. GreeneJM, LarinZ, TaylorIC, PrenticeH, GwinnKA, et al. (1987) Multiple basal elements of a human hsp70 promoter function differently in human and rodent cell lines. Mol Cell Biol 7 : 3646–3655.
18. AbravayaK, PhillipsB, MorimotoRI (1991) Heat shock-induced interactions of heat shock transcription factor and the human hsp70 promoter examined by in vivo footprinting. Mol Cell Biol 11 : 586–592.
19. MorimotoRI (2008) Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev 22 : 1427–1438.
20. PrahladV, CorneliusT, MorimotoRI (2008) Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons. Science 320 : 811–814.
21. Ben-ZviA, MillerEA, MorimotoRI (2009) Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc Natl Acad Sci U S A 106 : 14914–14919.
22. HsuAL, MurphyCT, KenyonC (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300 : 1142–1145.
23. XiaoX, ZuoX, DavisAA, McMillanDR, CurryBB, et al. (1999) HSF1 is required for extra-embryonic development, postnatal growth and protection during inflammatory responses in mice. EMBO J 18 : 5943–5952.
24. JedlickaP, MortinMA, WuC (1997) Multiple functions of Drosophila heat shock transcription factor in vivo. EMBO J 16 : 2452–2462.
25. Parker-ThornburgJ, BonnerJJ (1987) Mutations that induce the heat shock response of Drosophila. Cell 51 : 763–772.
26. BonnerJJ, ParksC, Parker-ThornburgJ, MortinMA, PelhamHR (1984) The use of promoter fusions in Drosophila genetics: isolation of mutations affecting the heat shock response. Cell 37 : 979–991.
27. SilvaMC, FoxS, BeamM, ThakkarH, AmaralMD, et al. (2011) A genetic screening strategy identifies novel regulators of the proteostasis network. PLoS Genet 7: e1002438 doi:10.1371/journal.pgen.1002438.
28. NollenEA, GarciaSM, van HaaftenG, KimS, ChavezA, et al. (2004) Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci U S A 101 : 6403–6408.
29. ShoreDE, CarrCE, RuvkunG (2012) Induction of cytoprotective pathways is central to the extension of lifespan conferred by multiple longevity pathways. PLoS Genet 8: e1002792 doi:10.1371/journal.pgen.1002792.
30. MeloJA, RuvkunG (2012) Inactivation of conserved C. elegans genes engages pathogen - and xenobiotic-associated defenses. Cell 149 : 452–466.
31. WangMC, MinW, FreudigerCW, RuvkunG, XieXS (2011) RNAi screening for fat regulatory genes with SRS microscopy. Nat Methods 8 : 135–138.
32. CurranSP, RuvkunG (2007) Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet 3: e56 doi:10.1371/journal.pgen.0030056.
33. HansenM, HsuAL, DillinA, KenyonC (2005) New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet 1: e17 doi:10.1371/journal.pgen.0010017.
34. WangJ, Robida-StubbsS, TulletJM, RualJF, VidalM, et al. (2010) RNAi screening implicates a SKN-1-dependent transcriptional response in stress resistance and longevity deriving from translation inhibition. PLoS Genet 6: e1001048 doi:10.1371/journal.pgen.1001048.
35. KamathRS, FraserAG, DongY, PoulinG, DurbinR, et al. (2003) Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421 : 231–237.
36. KapulkinWJ, HiesterBG, LinkCD (2005) Compensatory regulation among ER chaperones in C. elegans. FEBS Lett 579 : 3063–3068.
37. CalfonM, ZengH, UranoF, TillJH, HubbardSR, et al. (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415 : 92–96.
38. KhalequeMA, BhartiA, GongJ, GrayPJ, SachdevV, et al. (2008) Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1. Oncogene 27 : 1886–1893.
39. MurawskaM, HasslerM, Renkawitz-PohlR, LadurnerA, BrehmA (2011) Stress-induced PARP activation mediates recruitment of Drosophila Mi-2 to promote heat shock gene expression. PLoS Genet 7: e1002206 doi: 10.1371/journal.pgen.1002206.
40. Hajdu-CroninYM, ChenWJ, SternbergPW (2004) The L-type cyclin CYL-1 and the heat-shock-factor HSF-1 are required for heat-shock-induced protein expression in Caenorhabditis elegans. Genetics 168 : 1937–1949.
41. NeefDW, TurskiML, ThieleDJ Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol 8: e1000291 doi:10.1371/journal.pbio.1000291.
42. GuisbertE, HermanC, LuCZ, GrossCA (2004) A chaperone network controls the heat shock response in E. coli. Genes Dev 18 : 2812–2821.
43. PoritzMA, BernsteinHD, StrubK, ZopfD, WilhelmH, et al. (1990) An E. coli ribonucleoprotein containing 4.5S RNA resembles mammalian signal recognition particle. Science 250 : 1111–1117.
44. ArnoldCE, WittrupKD (1994) The stress response to loss of signal recognition particle function in Saccharomyces cerevisiae. J Biol Chem 269 : 30412–30418.
45. ZhouM, WuX, GinsbergHN (1996) Evidence that a rapidly turning over protein, normally degraded by proteasomes, regulates hsp72 gene transcription in HepG2 cells. J Biol Chem 271 : 24769–24775.
46. MathewA, MathurSK, MorimotoRI (1998) Heat shock response and protein degradation: regulation of HSF2 by the ubiquitin-proteasome pathway. Mol Cell Biol 18 : 5091–5098.
47. TaubertS, HansenM, Van GilstMR, CooperSB, YamamotoKR (2008) The Mediator subunit MDT-15 confers metabolic adaptation to ingested material. PLoS Genet 4: e1000021 doi:10.1371/journal.pgen.1000021.
48. BadenhorstP, VoasM, RebayI, WuC (2002) Biological functions of the ISWI chromatin remodeling complex NURF. Genes Dev 16 : 3186–3198.
49. KipreosET (2005) Ubiquitin-mediated pathways in C. elegans. WormBook 1–24.
50. AndersonLL, MaoX, ScottBA, CrowderCM (2009) Survival from hypoxia in C. elegans by inactivation of aminoacyl-tRNA synthetases. Science 323 : 630–633.
51. SegrefA, TorresS, HoppeT (2011) A screenable in vivo assay to study proteostasis networks in Caenorhabditis elegans. Genetics 187 : 1235–1240.
52. LinkCD, CypserJR, JohnsonCJ, JohnsonTE (1999) Direct observation of stress response in Caenorhabditis elegans using a reporter transgene. Cell Stress Chaperones 4 : 235–242.
53. MurphyCT, McCarrollSA, BargmannCI, FraserA, KamathRS, et al. (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424 : 277–283.
54. CarusoME, JennaS, BouchecareilhM, BaillieDL, BoismenuD, et al. (2008) GTPase-mediated regulation of the unfolded protein response in Caenorhabditis elegans is dependent on the AAA+ ATPase CDC-48. Mol Cell Biol 28 : 4261–4274.
55. ZhongW, SternbergPW (2006) Genome-wide prediction of C. elegans genetic interactions. Science 311 : 1481–1484.
56. NewmanME, GirvanM (2004) Finding and evaluating community structure in networks. Phys Rev E Stat Nonlin Soft Matter Phys 69 : 026113.
57. GuimeraR, AmaralLA (2005) Cartography of complex networks: modules and universal roles. J Stat Mech 2005: nihpa35573.
58. YonedaT, BenedettiC, UranoF, ClarkSG, HardingHP, et al. (2004) Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J Cell Sci 117 : 4055–4066.
59. RonD, WalterP (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8 : 519–529.
60. ReddyPS, CorleyRB (1999) The contribution of ER quality control to the biologic functions of secretory IgM. Immunol Today 20 : 582–588.
61. DunnAY, MelvilleMW, FrydmanJ (2001) Review: cellular substrates of the eukaryotic chaperonin TRiC/CCT. J Struct Biol 135 : 176–184.
62. BrennerS (1974) The genetics of Caenorhabditis elegans. Genetics 77 : 71–94.
63. McKaySJ, JohnsenR, KhattraJ, AsanoJ, BaillieDL, et al. (2003) Gene expression profiling of cells, tissues, and developmental stages of the nematode C. elegans. Cold Spring Harb Symp Quant Biol 68 : 159–169.
64. HarrisTW, AntoshechkinI, BieriT, BlasiarD, ChanJ, et al. WormBase: a comprehensive resource for nematode research. Nucleic Acids Res 38: D463–467.
65. Hall DH, Altun ZF (2008) C. elegans atlas. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press. x, 348 p. p.
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