BioPAX pathway converted from "Trimerization of cytosolic HSF1" in the Reactome database.Trimerization of cytosolic HSF1

Trimerization of cytosolic HSF1

Accumulation of non-native or misfolded proteins upon cellular stress is believed to release monomeric HSF1 from chaperon regulatory proteins (Guo Y et al. 2001). The released HSF1 monomer is rapidly converted to a homotrimer (Baler R et al. 1993; Herbomel G et al 2013). Upon trimerization HSF1 undergoes significant conformational changes resulting in an assembly of a stable triple-stranded alpha-helical coiled-coil structure with the amino-terminal hydrophobic domains from individual monomeric units (Rabindran SK et al. 1993; Zuo J et al. 1994, 1995; Neef DW et al. 2013). Biochemical and structural analysis strongly suggest that the monomer-to-trimer transition is tightly regulated at several interdependent levels. Thus, HSPs and cofactors bind HSF1 monomers preventing trimerization (Zou J et al.1998; Guo Y et al. 2001). In addition, leucine zippers (LZ) in the trimerization domain (LZ1-LZ3) are thought to retain HSF1 in its inactive monomeric form by intramolecular coiled-coil interactions with LZ4 in the carboxyl-terminus of HSF1, while LZ interactions between trimerization domains of individual monomeric units facilitate homotrimerization (Rabindran SK et al. 1993; Zuo J et al. 1994, 1995; Neef DW et al. 2013). HSF1 flexible linker region between DNA binding domain and first LZ of the trimerization domain was also found to modulate the monomer-trimer equilibrium (Liu PCC and Thiele DJ 1999). Furthermore, intermolecular disulfide bonds between cysteine residues 36 and 103 were reported to stabilize HSF1 trimer, while intramolecular disulfide crosslink inhibited HSF1 oligomerization (Lu M et al. 2008, 2009). Moreover, redox regulatory mechanisms were shown to regulate thiol-disulfide exchange and the conformation and activity of mammalian HSF1 in response to stress (Manalo DJ et al. 2002; Ahn SG and Thiele DJ 2003).<p>A ribonucleoprotein complex containing translation elongation factor EEF1A1 (eEF1A) and a long non-coding RNA, HSR1 (heat shock RNA-1) was shown to mediate trimerization of HSF1 (Shamovsky I et al. 2006).

Authored: Shamovsky, V, 2013-10-28Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

Reactome DB_ID: 3371452

cytosolGO0005829

UniProt:Q00613 HSF1

HSF1

HSF1HSTF1FUNCTION Functions as a stress-inducible and DNA-binding transcription factor that plays a central role in the transcriptional activation of the heat shock response (HSR), leading to the expression of a large class of molecular chaperones heat shock proteins (HSPs) that protect cells from cellular insults' damage (PubMed:1871105, PubMed:11447121, PubMed:1986252, PubMed:7760831, PubMed:7623826, PubMed:8946918, PubMed:8940068, PubMed:9341107, PubMed:9121459, PubMed:9727490, PubMed:9499401, PubMed:9535852, PubMed:12659875, PubMed:12917326, PubMed:15016915, PubMed:25963659, PubMed:26754925). In unstressed cells, is present in a HSP90-containing multichaperone complex that maintains it in a non-DNA-binding inactivated monomeric form (PubMed:9727490, PubMed:11583998, PubMed:16278218). Upon exposure to heat and other stress stimuli, undergoes homotrimerization and activates HSP gene transcription through binding to site-specific heat shock elements (HSEs) present in the promoter regions of HSP genes (PubMed:1871105, PubMed:1986252, PubMed:8455624, PubMed:7935471, PubMed:7623826, PubMed:8940068, PubMed:9727490, PubMed:9499401, PubMed:10359787, PubMed:11583998, PubMed:12659875, PubMed:16278218, PubMed:25963659, PubMed:26754925). Activation is reversible, and during the attenuation and recovery phase period of the HSR, returns to its unactivated form (PubMed:11583998, PubMed:16278218). Binds to inverted 5'-NGAAN-3' pentamer DNA sequences (PubMed:1986252, PubMed:26727489). Binds to chromatin at heat shock gene promoters (PubMed:25963659). Plays also several other functions independently of its transcriptional activity. Involved in the repression of Ras-induced transcriptional activation of the c-fos gene in heat-stressed cells (PubMed:9341107). Positively regulates pre-mRNA 3'-end processing and polyadenylation of HSP70 mRNA upon heat-stressed cells in a symplekin (SYMPK)-dependent manner (PubMed:14707147). Plays a role in nuclear export of stress-induced HSP70 mRNA (PubMed:17897941). Plays a role in the regulation of mitotic progression (PubMed:18794143). Plays also a role as a negative regulator of non-homologous end joining (NHEJ) repair activity in a DNA damage-dependent manner (PubMed:26359349). Involved in stress-induced cancer cell proliferation in a IER5-dependent manner (PubMed:26754925).FUNCTION (Microbial infection) Plays a role in latent human immunodeficiency virus (HIV-1) transcriptional reactivation. Binds to the HIV-1 long terminal repeat promoter (LTR) to reactivate viral transcription by recruiting cellular transcriptional elongation factors, such as CDK9, CCNT1 and EP300.SUBUNIT Monomer; cytoplasmic latent and transcriptionally inactive monomeric form in unstressed cells (PubMed:8455624, PubMed:7935376, PubMed:7935471, PubMed:7623826, PubMed:9222587, PubMed:9727490, PubMed:11583998). Homotrimer; in response to stress, such as heat shock, homotrimerizes and translocates into the nucleus, binds to heat shock element (HSE) sequences in promoter of heat shock protein (HSP) genes and acquires transcriptional ability (PubMed:8455624, PubMed:7935471, PubMed:7623826, PubMed:9222587, PubMed:9727490, PubMed:11583998, PubMed:26754925, PubMed:26727489). Interacts (via monomeric form) with FKBP4; this interaction occurs in unstressed cells (PubMed:11583998). Associates (via monomeric form) with HSP90 proteins in a multichaperone complex in unnstressed cell; this association maintains HSF1 in a non-DNA-binding and transcriptional inactive form by preventing HSF1 homotrimerization (PubMed:9727490, PubMed:11583998, PubMed:15661742, PubMed:16278218). Homotrimeric transactivation activity is modulated by protein-protein interactions and post-translational modifications (PubMed:11583998, PubMed:15016915, PubMed:16554823, PubMed:26754925). Interacts with HSP90AA1; this interaction is decreased in a IER5-dependent manner, promoting HSF1 accumulation in the nucleus, homotrimerization and DNA-binding activities (PubMed:26754925). Part (via regulatory domain in the homotrimeric form) of a large heat shock-induced HSP90-dependent multichaperone complex at least composed of FKBP4, FKBP5, HSP90 proteins, PPID, PPP5C and PTGES3; this association maintains the HSF1 homotrimeric DNA-bound form in a transcriptionally inactive form (PubMed:9727490, PubMed:11583998, PubMed:16278218). Interacts with BAG3 (via BAG domain); this interaction occurs in normal and heat-shocked cells promoting nuclear shuttling of HSF1 in a BAG3-dependent manner (PubMed:26159920). Interacts (via homotrimeric and hyperphosphorylated form) with FKBP4; this interaction occurs upon heat shock in a HSP90-dependent multichaperone complex (PubMed:11583998). Interacts (via homotrimeric form preferentially) with EEF1A proteins (PubMed:15016915). In heat shocked cells, stress-denatured proteins compete with HSF1 homotrimeric DNA-bound form for association of the HSP90-dependent multichaperone complex, and hence alleviating repression of HSF1-mediated transcriptional activity (PubMed:11583998). Interacts (via homotrimeric form preferentially) with DAXX; this interaction relieves homotrimeric HSF1 from repression of its transcriptional activity by HSP90-dependent multichaperone complex upon heat shock (PubMed:15016915). Interacts (via D domain and preferentially with hyperphosphorylated form) with JNK1; this interaction occurs under both normal growth conditions and immediately upon heat shock (PubMed:10747973). Interacts (via D domain and preferentially with hyperphosphorylated form) with MAPK3; this interaction occurs upon heat shock (PubMed:10747973). Interacts with IER5 (via central region); this interaction promotes PPP2CA-induced dephosphorylation on Ser-121, Ser-307, Ser-314, Thr-323 and Thr-367 and HSF1 transactivation activity (PubMed:25816751, PubMed:26496226, PubMed:26754925). Found in a ribonucleoprotein complex composed of the HSF1 homotrimeric form, translation elongation factor eEF1A proteins and non-coding RNA heat shock RNA-1 (HSR1); this complex occurs upon heat shock and stimulates HSF1 DNA-binding activity (PubMed:16554823). Interacts (via transactivation domain) with HSPA1A/HSP70 and DNAJB1; these interactions result in the inhibition of heat shock- and HSF1-induced transcriptional activity during the attenuation and recovery phase from heat shock (PubMed:7935376, PubMed:9222587, PubMed:9499401). Interacts (via Ser-303 and Ser-307 phosphorylated form) with YWHAE; this interaction promotes HSF1 sequestration in the cytoplasm in an ERK-dependent manner (PubMed:12917326). Found in a complex with IER5 and PPP2CA (PubMed:26754925). Interacts with TPR; this interaction increases upon heat shock and stimulates export of HSP70 mRNA (PubMed:17897941). Interacts with SYMPK (via N-terminus) and CSTF2; these interactions occur upon heat shock (PubMed:14707147). Interacts (via transactivation domain) with HSPA8 (PubMed:9499401). Interacts with EEF1D; this interaction occurs at heat shock promoter element (HSE) sequences (PubMed:21597468). Interacts with MAPKAPK2 (PubMed:16278218). Interacts with PRKACA/PKA (PubMed:21085490). Interacts (via transactivation domain) with GTF2A2 (PubMed:11005381). Interacts (via transactivation domain) with GTF2B (PubMed:11005381). Interacts (via transactivation domain) with TBP (PubMed:11005381). Interacts with CDK9, CCNT1 and EP300 (PubMed:27189267). Interacts (via N-terminus) with XRCC5 (via N-terminus) and XRCC6 (via N-terminus); these interactions are direct and prevent XRCC5/XRCC6 heterodimeric binding and non-homologous end joining (NHEJ) repair activities induced by ionizing radiation (IR) (PubMed:26359349). Interacts with PLK1; this interaction occurs during the early mitotic period, increases upon heat shock but does not modulate neither HSF1 homotrimerization and DNA-binding activities (PubMed:15661742, PubMed:18794143). Interacts (via Ser-216 phosphorylated form) with CDC20; this interaction occurs in mitosis in a MAD2L1-dependent manner and prevents PLK1-stimulated degradation of HSF1 by blocking the recruitment of the SCF(BTRC) ubiquitin ligase complex (PubMed:18794143). Interacts with MAD2L1; this interaction occurs in mitosis (PubMed:18794143). Interacts with BTRC; this interaction occurs during mitosis, induces its ubiquitin-dependent degradation following stimulus-dependent phosphorylation at Ser-216, a process inhibited by CDC20 (PubMed:18794143). Interacts with HSP90AA1 and HSP90AB1 (PubMed:26517842).DOMAIN In unstressed cells, spontaneous homotrimerization is inhibited (PubMed:7935471, PubMed:7760831). Intramolecular interactions between the hydrophobic repeat HR-A/B and HR-C regions are necessary to maintain HSF1 in the inactive, monomeric conformation (PubMed:7935471, PubMed:7623826). Furthermore, intramolecular interactions between the regulatory domain and the nonadjacent transactivation domain prevents transcriptional activation, a process that is relieved upon heat shock (PubMed:7760831). The regulatory domain is necessary for full repression of the transcriptional activation domain in unstressed cells through its phosphorylation on Ser-303 and Ser-307 (PubMed:8946918, PubMed:9121459). In heat stressed cells, HSF1 homotrimerization occurs through formation of a three-stranded coiled-coil structure generated by intermolecular interactions between HR-A/B regions allowing DNA-binding activity (PubMed:7935471). The D domain is necessary for translocation to the nucleus, interaction with JNK1 and MAPK3 and efficient JNK1- and MAPK3-dependent phosphorylation (PubMed:10747973). The regulatory domain confers heat shock inducibility on the transcriptional transactivation domain (PubMed:7760831). The regulatory domain is necessary for transcriptional activation through its phosphorylation on Ser-230 upon heat shock (PubMed:11447121). 9aaTAD is a transactivation motif present in a large number of yeast and animal transcription factors (PubMed:17467953).PTM Phosphorylated (PubMed:9499401, PubMed:10359787, PubMed:11583998, PubMed:26159920). Phosphorylated in unstressed cells; this phosphorylation is constitutive and implicated in the repression of HSF1 transcriptional activity (PubMed:8946918, PubMed:8940068, PubMed:9121459, PubMed:16278218). Phosphorylated on Ser-121 by MAPKAPK2; this phosphorylation promotes interaction with HSP90 proteins and inhibits HSF1 homotrimerization, DNA-binding and transactivation activities (PubMed:16278218). Phosphorylation on Ser-303 by GSK3B/GSK3-beta and on Ser-307 by MAPK3 within the regulatory domain is involved in the repression of HSF1 transcriptional activity and occurs in a RAF1-dependent manner (PubMed:8946918, PubMed:8940068, PubMed:9121459, PubMed:9535852, PubMed:10747973, PubMed:12646186). Phosphorylation on Ser-303 and Ser-307 increases HSF1 nuclear export in a YWHAE- and XPO1/CRM1-dependent manner (PubMed:12917326). Phosphorylation on Ser-307 is a prerequisite for phosphorylation on Ser-303 (PubMed:8940068). According to PubMed:9535852, Ser-303 is not phosphorylated in unstressed cells. Phosphorylated on Ser-419 by PLK1; phosphorylation promotes nuclear translocation upon heat shock (PubMed:15661742). Hyperphosphorylated upon heat shock and during the attenuation and recovery phase period of the heat shock response (PubMed:11447121, PubMed:12659875, PubMed:24581496). Phosphorylated on Thr-142; this phosphorylation increases HSF1 transactivation activity upon heat shock (PubMed:12659875). Phosphorylation on Ser-230 by CAMK2A; this phosphorylation enhances HSF1 transactivation activity upon heat shock (PubMed:11447121). Phosphorylation on Ser-326 by MAPK12; this phosphorylation enhances HSF1 nuclear translocation, homotrimerization and transactivation activities upon heat shock (PubMed:15760475, PubMed:27354066). Phosphorylated on Ser-320 by PRKACA/PKA; this phosphorylation promotes nuclear localization and transcriptional activity upon heat shock (PubMed:21085490). Phosphorylated on Ser-363 by MAPK8; this phosphorylation occurs upon heat shock, induces HSF1 translocation into nuclear stress bodies and negatively regulates transactivation activity (PubMed:10747973). Neither basal nor stress-inducible phosphorylation on Ser-230, Ser-292, Ser-303, Ser-307, Ser-314, Ser-319, Ser-320, Thr-323, Ser-326, Ser-338, Ser-344, Ser-363, Thr-367, Ser-368 and Thr-369 within the regulatory domain is involved in the regulation of HSF1 subcellular localization or DNA-binding activity; however, it negatively regulates HSF1 transactivation activity (PubMed:25963659). Phosphorylated on Ser-216 by PLK1 in the early mitotic period; this phosphorylation regulates HSF1 localization to the spindle pole, the recruitment of the SCF(BTRC) ubiquitin ligase complex inducing HSF1 degradation, and hence mitotic progression (PubMed:18794143). Dephosphorylated on Ser-121, Ser-307, Ser-314, Thr-323 and Thr-367 by phosphatase PPP2CA in an IER5-dependent manner, leading to HSF1-mediated transactivation activity (PubMed:26754925).PTM Sumoylated with SUMO1 and SUMO2 upon heat shock in a ERK2-dependent manner (PubMed:12646186, PubMed:12665592). Sumoylated by SUMO1 on Lys-298; sumoylation occurs upon heat shock and promotes its localization to nuclear stress bodies and DNA-binding activity (PubMed:11514557). Phosphorylation on Ser-303 and Ser-307 is probably a prerequisite for sumoylation (PubMed:12646186, PubMed:12665592).PTM Acetylated on Lys-118; this acetylation is decreased in a IER5-dependent manner (PubMed:26754925). Acetylated on Lys-118, Lys-208 and Lys-298; these acetylations occur in a EP300-dependent manner (PubMed:24581496, PubMed:27189267). Acetylated on Lys-80; this acetylation inhibits DNA-binding activity upon heat shock (PubMed:19229036). Deacetylated on Lys-80 by SIRT1; this deacetylation increases DNA-binding activity (PubMed:19229036).PTM Ubiquitinated by SCF(BTRC) and degraded following stimulus-dependent phosphorylation at Ser-216 by PLK1 in mitosis (PubMed:18794143). Polyubiquitinated (PubMed:24581496). Undergoes proteasomal degradation upon heat shock and during the attenuation and recovery phase period of the heat shock response (PubMed:24581496).SIMILARITY Belongs to the HSF family.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtQ00613

Chain Coordinates

EQUAL

529

EQUAL

Reactome DB_ID: 4793915

HSF1 trimer [cytosol]

HSF1 trimer

Reactome DB_ID: 4793916

Inter-chain Crosslink via L-cystine (cross-link) at 103 and 36

103

EQUAL

L-cystine (cross-link)ChEBI50058

modification

Inter-chain Crosslink via L-cystine (cross-link) at 36 and 103

EQUAL

529

EQUAL

Reactome Database ID Release 754793915Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4793915ReactomeR-HSA-4793915

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4793915.1Reactome Database ID Release 753371591Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3371591ReactomeR-HSA-3371591

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3371591.311851405Pubmed2002Redox-dependent regulation of the conformation and function of human heat shock factor 1Manalo, Dominador JLin, ZhengLiu, Alice Y-CBiochemistry 41:2580-818457423Pubmed2008Two distinct disulfide bonds formed in human heat shock transcription factor 1 act in opposition to regulate its DNA binding activityLu, MingKim, Hee-EunLi, Chun-RiKim, SolKwak, Im-JungLee, Yun-JuKim, So-SunMoon, Ji-YoungKim, Cho HeeKim, Dong-KyooKang, Ho SungPark, Jang-SuBiochemistry 47:6007-157623826Pubmed1995Multiple layers of regulation of human heat shock transcription factor 1Zuo, JRungger, DVoellmy, RMol. Cell. Biol. 15:4319-3019338268Pubmed2009Aromatic-participant interactions are essential for disulfide-bond-based trimerization in human heat shock transcription factor 1Lu, MingLee, Yun-JuPark, Sung-MinKang, Ho SungKang, Shin WonKim, SuhkmannPark, Jang-SuBiochemistry 48:3795-78421783Pubmed1993Regulation of heat shock factor trimer formation: role of a conserved leucine zipperRabindran, S KHaroun, R IClos, JWisniewski, JWu, CScience 259:230-412600944Pubmed2003Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stressAhn, Sang-GunThiele, Dennis JGenes Dev. 17:516-289727490Pubmed1998Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1Zou, JGuo, YGuettouche, TSmith, David FVoellmy, RCell 94:471-8016554823Pubmed2006RNA-mediated response to heat shock in mammalian cellsShamovsky, IlyaIvannikov, MaximKandel, Eugene SGershon, DavidNudler, EvgenyNature 440:556-6023861773Pubmed2013Dynamics of the full length and mutated heat shock factor 1 in human cellsHerbomel, GaëtanKloster-Landsberg, MeikeFolco, Eric GCol, EdwigeUsson, YvesVourc'h, ClaireDelon, AntoineSouchier, CatherinePLoS ONE 8:e6756623733891Pubmed2013Genetic selection for constitutively trimerized human HSF1 mutants identifies a role for coiled-coil motifs in DNA bindingNeef, Daniel WJaeger, Alex MThiele, Dennis JG3 (Bethesda) 3:1315-2411583998Pubmed2001Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complexGuo, YGuettouche, TFenna, MBoellmann, FPratt, W BToft, D OSmith, David FVoellmy, RJ. Biol. Chem. 276:45791-97935471Pubmed1994Activation of the DNA-binding ability of human heat shock transcription factor 1 may involve the transition from an intramolecular to an intermolecular triple-stranded coiled-coil structureZuo, JBaler, RDahl, GVoellmy, RMol. Cell. Biol. 14:7557-6810358080Pubmed1999Modulation of human heat shock factor trimerization by the linker domainLiu, P CThiele, D JJ. Biol. Chem. 274:17219-258455624Pubmed1993Activation of human heat shock genes is accompanied by oligomerization, modification, and rapid translocation of heat shock transcription factor HSF1Baler, RDahl, GVoellmy, RMol. Cell. Biol. 13:2486-96

ACTIVATION

Reactome Database ID Release 754793637Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4793637ReactomeR-HSA-4793637

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4793637.1

Reactome DB_ID: 156905

UniProt:P68104 EEF1A1

EEF1A1

EEF1A1EF1AEEF1ALENG7FUNCTION This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis. Plays a role in the positive regulation of IFNG transcription in T-helper 1 cells as part of an IFNG promoter-binding complex with TXK and PARP1 (PubMed:17177976).SUBUNIT Found in a nuclear export complex with XPO5, EEF1A1, Ran and aminoacylated tRNA (PubMed:12426392, PubMed:12426393). Interacts with PARP1 and TXK (PubMed:17177976). Interacts with KARS1 (PubMed:18029264). May interact with ERGIC2. Interacts with IFIT1 (via TPR repeats 4-7) (By similarity). Interacts with DLC1, facilitating distribution to the membrane periphery and ruffles upon growth factor stimulation. Interacts with ZPR1; the interaction occurs in a epidermal growth factor (EGF)-dependent manner. Interacts with PPP1R16B (PubMed:26497934). Interacts with SPHK1 and SPHK2; both interactions increase SPHK1 and SPHK2 kinase activity (PubMed:18263879).TISSUE SPECIFICITY Brain, placenta, lung, liver, kidney, pancreas but barely detectable in heart and skeletal muscle.INDUCTION By homocysteine (HC), may mediate accelerated synthesis of free thiol-containing proteins in response to HC-induced oxidative stress.PTM ISGylated.PTM Phosphorylated by TXK. Phosphorylation by PASK increases translation efficiency. Phosphorylated by ROCK2 (PubMed:26497934).PTM Trimethylated at Lys-79 by EEF1AKMT1 (PubMed:26545399). Methylated at Lys-165 by EEF1AKMT3, methylation by EEF1AKMT3 is dynamic as well as inducible by stress conditions, such as ER-stress, and plays a regulatory role on mRNA translation (PubMed:28108655). Trimethylated at Lys-318 by EEF1AKMT2 (PubMed:25144183). Mono-, di-, and trimethylated at Lys-36 by EEF1AKMT4; trimethylated form is predominant. Methylation by EEF1AKMT4 contributes to the fine-tuning of translation rates for a subset of tRNAs (PubMed:28520920). Trimethylated at Gly-2 by EEF1AKNMT (PubMed:30143613). Mono- and dimethylated at Lys-55 by EEF1AKNMT; dimethylated form is predominant (PubMed:30143613, PubMed:30612740).SIMILARITY Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-Tu/EF-1A subfamily.

UniProtP68104

EQUAL

462

EQUAL