Cellular response to heat stress (Homo sapiens)

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22, 54132, 36, 4520, 47442431324399, 10, 33, 34, 38...5447, 515, 3750553854172, 3, 19, 363, 3625, 414, 2650136, 21, 28, 29, 4015, 42, 54312, 31, 5211, 54STRESScytosolnucleoplasmSTRESSCRYBA4 gene HSF1PiHSPA1L HSPA7 DEDD2 gene FKBP4 HSPA8 p-T185,Y187-MAPK1 ADPHSF1NUP155 p-S326-hC36,103-HSF1 HSPH1 HSPA6 gene SIRT1 HSF1:RPAHSPA7 TPR RANBP2 CREBBP Nuclear Pore Complex(NPC)DNAJC7 HSPA1L HSF1 trimerDNAJB1 HSBP1 gene HSPA1L CRYBA4 gene HSPA4 ATPHSPA1B DNAJB1 gene ATPNUPL1-2 TNFRSF21 gene GML gene NUP98-3 HSPA9 PiHSPA1L NDC1 HSPA14 p-S326-HSF1 trimerADPHSPA12A HSBP1 HSP90AA1 DNAJB6 gene HDAC6:VCP:proteinaggregatesHSPA8 DNAJB1,B6,C2,C7HSF1 trimer:targetgeneHSPA6 HSPA2 HSPA1B MRPL18 gene ATPEEF1A1p-S230-HSF1 trimerHSP90AA1 HSPA8 ATM DNAJB1 gene PTGES3 HSBP1 HSP90AB1 NUP35 NUP153 HSP90AB1 HSPA7 DNAJB6 gene HSF1 target geneHSPA13 NAMGML gene GML gene HSPA8 HSF1 Ac-K80-hC36,103-HSF1 HSPA1L HSP90AA1 HSPB2 gene COL4A6 gene UBB gene HSPA8 HSPA4L HSBP1 gene HSPA12A HSPA1L gene HSF1:HSP90:PTGES3HikeshiHSF1:HSP90:PTGES3FKBP4 RPTOR HSPA1A HSPA8 SERPINH1 gene HSPA14 DEDD2 gene HSP90AA1 p-S303,307-HSF1 HSPA2 HSPB2 gene HSPA1L mTORC1 dimerHSP70s:ADPDNAJB1 HSBP1 RLN1 gene DNAJB1 DNAJB1 gene ADPNAD+RPA2 CRYBA4 gene HSPA4L GML gene HSPA2 HSPA7 HSPA5 HSP90:FKBP4:PTGES3HSPH1 gene DNAJB1 FKBP4 gene RPA1 HSPA6 gene HDAC6 H2OHSP90AB1 HSPA1B hC36,103-HSF1 HSP90AA1 AKT1S1 UBB gene ATR HSPB2 gene RPA3 HSPA13 NUP88 HSPA1 gene HSPA4 Ub-protein aggregates NUP98-4 hC36,103-HSF1 GSK3BUBB gene HSPA6 gene HSPA4 YWHAE dimerDEDD2 gene RPS19BP1HSBP1 gene NUP210 DNAJB6 gene HSP70s:ATPDNAJB1 gene NUP133 HSPA14 UBB gene HSPA6 RPA3 TNFRSF21 gene EP300 HSPA5 HSPA8 ATP HSPA4 HSP90AB1 HSPA1L gene DNAJC2 HSPA12B SERPINH1 gene Ac-CoAHSPA1 gene HSP90AA1 p-T286-CAMK2A RLN1 gene p-S303,307-HSF1:YWHAEHSPA14 DNAJB6 gene HSP90:HSP90HSPA1 gene PTGES3 HSPA1A VCP RLN1 gene CoA-SHHSPH1 gene DNAJB6 HSPB2 gene NUP54 SIRT1 YWHAE HSPB2 gene GML gene TNFRSF21 gene HSP90:HSP90SERPINH1 gene HSPA8 HSPA6 HSPA12B VCP CRYAB MRPL18 gene DNAJB1 gene CREBBP, EP300HSPA1B PTGES3ADP PTGES3 HSPA6 gene HSPA6 gene BAG1-5 HSPA5 DNAJB6 gene HSPA5 HSPA1A DNAJB6 DNAJC2 ADP NUP43 Hikeship-S230-hC36,103-HSF1 HSPA1B HSPB2 gene HSPA12B HSBP1:HSF1 trimerNUP107 hC36,103-HSF1 RPA heterotrimerSIRT1:HSP70:DNAJB1:Ac-K80-HSF1:target geneHeat shock inducibleproteinsHSPA1B COL4A6 gene NUP37 HSP90AB1 HSPA5 HSP90AB1 MRPL18 gene p-S307-HSF1p-T,Y MAPK dimersHSP90AA1 PTGES3HSPB2 gene CRYBA4 gene HSPA2 ATP p-S121-HSF1p-T287-CAMK2D HSPA1B DBC1SERPINH1 gene NUP85 HSP90AA1 H2ODNAJB1 gene HSPA1A YWHAE HSP70:DNAJB1:HSF1trimer:target geneTNFRSF21 gene p-T287-CAMK2G HSP70 NEFsHSPA9 COL4A6 gene hC36,103-HSF1 HSPA6 HSPA8 HSPA1 gene HSPA4L DNAJB1 HSPA1B HSPA1 gene DNAJB6 gene DEDD2 gene HSPA1A NUP98-5 HSPA1L HSPA1L HSPA1L gene HSPA6 HSPA1A HSPB2 gene HSPA2 HSPA1L Ac-K80-hC36,103-HSF1 HSF1 target geneFKBP4 gene TNFRSF21 gene HSPA7 HSPA1B NUP62 HSPH1 gene HSPB8 HSPA1L gene HSP90AB1 HSPA2 HSPA12B HSPA1L gene HSPA13 HSPA9 UBB gene HSPA1A HSPB2 gene HSPA12A hC36,103-HSF1 Hikeshi:HSP70s:ATPSEH1L-2 DNAJB1,B6,C2,C7FKBP4 gene p-T454-DBC1 HSP70:DNAJB1HSP70s:ADPNUP50 HSP70:DNAJB1:Ac-K80-HSF1HSPA1A ATP DNAJB1 HSPA8 DNAJB1 HSPA12B ATPHSPA1A HDAC6 GML gene NUP93 p-S303-HSF1HSPA6 gene MRPL18 gene p-S303,307-HSF1H2OHSPA2 HSPA13 NUP205 HSPB2 gene HSPA2 p-T287-CAMK2B MTOR RPA1 HSPA12A HSPA4L HSPA8 HSPA1B Hikeshi HSPA13 POM121 HSPA1L p-T454-DBC1:SIRT1AAAS HSP90AB1 NUP160 HSPA1A RLN1 gene CRYBA4 gene hC36,103-HSF1 HSPA9 CRYBA4 gene hC36,103-HSF1 RPA2 RAE1 ADPADPFKBP4 gene PTGES3 CaMKIIHSPB2 gene HSPA2 Hikeshi:HSP70s:ATPSIRT1NUP214 HSBP1 gene HSF1 trimerMRPL18 gene Ub-proteinaggregatesHSPA1L gene COL4A6 gene ATPHSP70:DNAJB1:Ac-K80-HSF1 trimer:target geneHSPA4 HSPA12A HSPA1B DNAJC7 NUPL2 HSPA1L COL4A6 gene FKBP4 gene DEDD2 gene ST13 tetramerNUP188 HSPA1 gene DEDD2 gene ST13 HSBP1 gene MRPL18 gene TNFRSF21 gene SIRT1p-T454-DBC1p-T202,Y204-MAPK3 Nup45 2'-O-acetyl-ADP-riboseHSBP1 gene MAPKAPK2HSPA1A HSF1 HSPH1 gene HSF1 UBB gene RLN1 gene ATM/ATR kinaseSERPINH1 gene RLN1 gene HSBP1 hexamerDNAJB1 HSPH1 gene PTGES3 Hikeshi HSF1:HSP90:HDAC6:VCP:PTGES3MLST8 COL4A6 gene POM121C SERPINH1 gene HSPA9 HSF1trimer:HSP90:FKBP4:PTGES3FKBP4 gene HSPA14 HSPA2 Ac-K80-hC36,103-HSF1 HSPB2 gene HSPH1 gene HSPA4L 84442, 48482632, 45273714, 37, 50, 53121217123914, 37, 39, 50, 537, 18, 23, 3516, 433037, 50814, 37, 50, 535642, 48


In response to exposure to elevated temperature and certain other proteotoxic stimuli (e.g., hypoxia, free radicals) cells activate a number of cytoprotective mechanisms known collectively as "heat shock response". Major aspects of the heat shock response (HSR) are evolutionarily conserved events that allow cells to recover from protein damage induced by stress (Liu XD et al. 1997; Voellmy R & Boellmann F 2007; Shamovsky I & Nudler E 2008; Anckar J & Sistonen L 2011). The main hallmark of HSR is the dramatic alteration of the gene expression pattern. A diverse group of protein genes is induced by the exposure to temperatures 3-5 degrees higher than physiological. Functionally, most of these genes are molecular chaperones that ensure proper protein folding and quality control to maintain cell proteostasis.

At the same time, heat shock-induced phosphorylation of translation initiation factor eIF2alpha leads to the shutdown of the nascent polypeptide synthesis reducing the burden on the chaperone system that has to deal with the increased amount of misfolded and thermally denatured proteins (Duncan RF & Hershey JWB 1989; Sarkar A et al. 2002; Spriggs KA et al. 2010).<p>The induction of HS gene expression primarily occurs at the level of transcription and is mediated by heat shock transcription factor HSF1(Sarge KD et al. 1993; Baler R et al. 1993). Human cells express five members of HSF protein family: HSF1, HSF2, HSF4, HSFX and HSFY. HSF1 is the master regulator of the heat inducible gene expression (Zuo J et al. 1995; Akerfelt M et al. 2010). HSF2 is activated in response to certain developmental stimuli in addition to being co-activated with HSF1 to provide promoter-specific fine-tuning of the HS response by forming heterotrimers with HSF1 (Ostling P et al. 2007; Sandqvist A et al. 2009). HSF4 lacks the transcription activation domain and acts as a repressor of certain genes during HS (Nakai A et al. 1997; Tanabe M et al. 1999; Kim SA et al. 2012). Two additional family members HSFX and HSFY, which are located on the X and Y chromosomes respectively, remain to be characterized (Bhowmick BK et al. 2006; Shinka T et al. 2004; Kichine E et al. 2012).<p>Under normal conditions HSF1 is present in both cytoplasm and nucleus in the form of an inactive monomer. The monomeric state of HSF1 is maintained by an intricate network of protein-protein interactions that include the association with HSP90 multichaperone complex, HSP70/HSP40 chaperone machinery, as well as intramolecular interaction of two conserved hydrophobic repeat regions. Monomeric HSF1 is constitutively phosphorylated on Ser303 and Ser 307 by (Zou J et al. 1998; Knauf U et al. 1996; Kline MP & Moromoto RI 1997; Guettouche T et al. 2005). This phosphorylation plays an essential role in ensuring cytoplasmic localization of at least a subpopulation of HSF1 molecules under normal conditions (Wang X et al. 2004).<p>Exposure to heat and other proteotoxic stimuli results in the release of HSF1 from the inhibitory complex with chaperones and its subsequent trimerization, which is promoted by its interaction with translation elongation factor eEF1A1 (Baler R et al. 1993; Shamovsky I et al. 2006; Herbomel G et al 2013). The trimerization is believed to involve intermolecular interaction between hydrophobic repeats 1-3 leading to the formation of a triple coil structure. Additional stabilization of the HSF1 trimer is provided by the formation of intermolecular S-S bonds between Cys residues in the DNA binding domain (Lu M et al.2008). Trimeric HSF1 is predominantly localized in the nucleus where it binds the specific sequence in the promoter of hsp genes (Sarge KD et al. 1993; Wang Y and Morgan WD 1994). The binding sequence for HSF1 (HSE, heat shock element) contains series of inverted repeats nGAAn in head-to-tail orientation, with at least three elements being required for the high affinity binding. Binding of the HSF1 trimer to the promoter is not sufficient to induce transcription of the gene (Cotto J et al. 1996). In order to do so, HSF1 needs to undergo inducible phosphorylation on specific Ser residues such as Ser230, Ser326. This phosphorylated form of HSF1 trimer is capable of increasing the promoter initiation rate. HSF1 bound to DNA promotes recruiting components of the transcription mediator complex and relieving promoter-proximal pause of RNA polymerase II through its interaction with TFIIH transcription factor (Yuan CX & Gurley WB 2000).<p>HSF1 activation is regulated in a precise and tight manner at multiple levels (Zuo J et al. 1995; Cotto J et al. 1996). This allows fast and robust activation of HS response to minimize proteotoxic effects of the stress. The exact set of HSF1 inducible genes is probably cell type specific. Moreover, cells in different pathophysiological states will display different but overlapping profile of HS inducible genes. View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 3371556
Reactome version: 66
Reactome Author 
Reactome Author: Shamovsky, Veronica

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103018view15:33, 31 January 2019Mkutmonupdated outdated Ensembl identifier (HSPB2)
101444view11:31, 1 November 2018ReactomeTeamreactome version 66
100982view21:09, 31 October 2018ReactomeTeamreactome version 65
100518view19:43, 31 October 2018ReactomeTeamreactome version 64
100064view16:27, 31 October 2018ReactomeTeamreactome version 63
99616view15:00, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99224view12:44, 31 October 2018ReactomeTeamreactome version 62
93904view13:43, 16 August 2017ReactomeTeamreactome version 61
93477view11:24, 9 August 2017ReactomeTeamreactome version 61
87158view19:15, 18 July 2016MkutmonOntology Term : 'stress response pathway' added !
86574view09:21, 11 July 2016ReactomeTeamreactome version 56
83398view11:07, 18 November 2015ReactomeTeamVersion54
81593view13:08, 21 August 2015ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
2'-O-acetyl-ADP-riboseMetaboliteCHEBI:76279 (ChEBI)
AAAS ProteinQ9NRG9 (Uniprot-TrEMBL)
ADP MetaboliteCHEBI:16761 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT1S1 ProteinQ96B36 (Uniprot-TrEMBL)
ATM ProteinQ13315 (Uniprot-TrEMBL)
ATM/ATR kinaseComplexR-HSA-421853 (Reactome)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
ATR ProteinQ13535 (Uniprot-TrEMBL)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
Ac-K80-hC36,103-HSF1 ProteinQ00613 (Uniprot-TrEMBL)
BAG1-5 R-HSA-5255433 (Reactome)
COL4A6 gene ProteinENSG00000197565 (Ensembl)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CREBBP, EP300ComplexR-HSA-1027362 (Reactome)
CRYAB ProteinP02511 (Uniprot-TrEMBL)
CRYBA4 gene ProteinENSG00000196431 (Ensembl)
CaMKIIComplexR-HSA-444796 (Reactome)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DBC1ProteinQ8N163 (Uniprot-TrEMBL)
DEDD2 gene ProteinENSG00000160570 (Ensembl)
DNAJB1 ProteinP25685 (Uniprot-TrEMBL)
DNAJB1 gene ProteinENSG00000132002 (Ensembl)
DNAJB1,B6,C2,C7ComplexR-HSA-5252070 (Reactome)
DNAJB1,B6,C2,C7ComplexR-HSA-5255406 (Reactome)
DNAJB6 ProteinO75190 (Uniprot-TrEMBL)
DNAJB6 gene ProteinENSG00000105993 (Ensembl)
DNAJC2 ProteinQ99543 (Uniprot-TrEMBL)
DNAJC7 ProteinQ99615 (Uniprot-TrEMBL)
EEF1A1ProteinP68104 (Uniprot-TrEMBL)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
FKBP4 ProteinQ02790 (Uniprot-TrEMBL)
FKBP4 gene ProteinENSG00000004478 (Ensembl)
GML gene ProteinENSG00000104499 (Ensembl)
GSK3BProteinP49841 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HDAC6 ProteinQ9UBN7 (Uniprot-TrEMBL)
HDAC6:VCP:protein aggregatesComplexR-HSA-5324663 (Reactome)
HSBP1 ProteinO75506 (Uniprot-TrEMBL)
HSBP1 gene ProteinENSG00000106211 (Ensembl)
HSBP1 hexamerComplexR-HSA-3371426 (Reactome)
HSBP1:HSF1 trimerComplexR-HSA-5082413 (Reactome)
HSF1 trimer:HSP90:FKBP4:PTGES3ComplexR-HSA-5324619 (Reactome)
HSF1 ProteinQ00613 (Uniprot-TrEMBL)
HSF1 target geneComplexR-HSA-4793834 (Reactome)
HSF1 trimer:target geneComplexR-HSA-4793813 (Reactome)
HSF1 trimerComplexR-HSA-4793790 (Reactome)
HSF1 trimerComplexR-HSA-4793915 (Reactome)
HSF1:HSP90:HDAC6:VCP:PTGES3ComplexR-HSA-5324677 (Reactome)
HSF1:HSP90:PTGES3ComplexR-HSA-4793919 (Reactome)
HSF1:HSP90:PTGES3ComplexR-HSA-5082410 (Reactome)
HSF1:RPAComplexR-HSA-5333048 (Reactome)
HSF1ProteinQ00613 (Uniprot-TrEMBL)
HSP70 NEFsComplexR-HSA-5255429 (Reactome)
HSP70:DNAJB1:Ac-K80-HSF1 trimer:target geneComplexR-HSA-5082373 (Reactome)
HSP70:DNAJB1:Ac-K80-HSF1ComplexR-HSA-5082365 (Reactome)
HSP70:DNAJB1:HSF1 trimer:target geneComplexR-HSA-5082415 (Reactome)
HSP70:DNAJB1ComplexR-HSA-5082372 (Reactome)
HSP70s:ADPComplexR-HSA-5252013 (Reactome)
HSP70s:ADPComplexR-HSA-5252057 (Reactome)
HSP70s:ATPComplexR-HSA-5252049 (Reactome)
HSP90:FKBP4:PTGES3ComplexR-HSA-5324622 (Reactome)
HSP90:HSP90ComplexR-HSA-3371429 (Reactome)
HSP90:HSP90ComplexR-HSA-5082395 (Reactome)
HSP90AA1 ProteinP07900 (Uniprot-TrEMBL)
HSP90AB1 ProteinP08238 (Uniprot-TrEMBL)
HSPA1 gene R-HSA-4793808 (Reactome)
HSPA12A ProteinO43301 (Uniprot-TrEMBL)
HSPA12B ProteinQ96MM6 (Uniprot-TrEMBL)
HSPA13 ProteinP48723 (Uniprot-TrEMBL)
HSPA14 ProteinQ0VDF9 (Uniprot-TrEMBL)
HSPA1A ProteinP0DMV8 (Uniprot-TrEMBL)
HSPA1B ProteinP0DMV9 (Uniprot-TrEMBL)
HSPA1L ProteinP34931 (Uniprot-TrEMBL)
HSPA1L gene R-HSA-4793806 (Reactome)
HSPA2 ProteinP54652 (Uniprot-TrEMBL)
HSPA4 ProteinP34932 (Uniprot-TrEMBL)
HSPA4L ProteinO95757 (Uniprot-TrEMBL)
HSPA5 ProteinP11021 (Uniprot-TrEMBL)
HSPA6 ProteinP17066 (Uniprot-TrEMBL)
HSPA6 gene ProteinENSG00000173110 (Ensembl)
HSPA7 ProteinP48741 (Uniprot-TrEMBL)
HSPA8 ProteinP11142 (Uniprot-TrEMBL)
HSPA9 ProteinP38646 (Uniprot-TrEMBL)
HSPB2 gene ProteinENSG00000170276 (Ensembl)
HSPB8 ProteinQ9UJY1 (Uniprot-TrEMBL)
HSPH1 ProteinQ92598 (Uniprot-TrEMBL)
HSPH1 gene ProteinENSG00000120694 (Ensembl)
Heat shock inducible proteinsComplexR-HSA-5096380 (Reactome)
Hikeshi ProteinQ53FT3 (Uniprot-TrEMBL)
Hikeshi:HSP70s:ATPComplexR-HSA-5252002 (Reactome)
Hikeshi:HSP70s:ATPComplexR-HSA-5252091 (Reactome)
HikeshiProteinQ53FT3 (Uniprot-TrEMBL)
MAPKAPK2ProteinP49137 (Uniprot-TrEMBL)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MRPL18 gene ProteinENSG00000112110 (Ensembl)
MTOR ProteinP42345 (Uniprot-TrEMBL)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NAMMetaboliteCHEBI:17154 (ChEBI)
NDC1 ProteinQ9BTX1 (Uniprot-TrEMBL)
NUP107 ProteinP57740 (Uniprot-TrEMBL)
NUP133 ProteinQ8WUM0 (Uniprot-TrEMBL)
NUP153 Protein