In unstressed cells, spontaneous homotrimerization is inhibited (PubMed:7760831, PubMed:7935471). Intramolecular interactions between the hydrophobic repeat HR-A/B and HR-C regions are necessary to maintain HSF1 in the inactive, monomeric conformation (PubMed:7623826, PubMed:7935471). 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).
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 insult damage (PubMed:11447121, PubMed:12659875, PubMed:12917326, PubMed:15016915, PubMed:18451878, PubMed:1871105, PubMed:1986252, PubMed:25963659, PubMed:26754925, PubMed:7623826, PubMed:7760831, PubMed:8940068, PubMed:8946918, PubMed:9121459, PubMed:9341107, PubMed:9499401, PubMed:9535852, PubMed:9727490). In unstressed cells, is present in a HSP90-containing multichaperone complex that maintains it in a non-DNA-binding inactivated monomeric form (PubMed:11583998, PubMed:16278218, PubMed:9727490). 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:10359787, PubMed:11583998, PubMed:12659875, PubMed:16278218, PubMed:1871105, PubMed:1986252, PubMed:25963659, PubMed:26754925, PubMed:7623826, PubMed:7935471, PubMed:8455624, PubMed:8940068, PubMed:9499401, PubMed:9727490). Upon heat shock stress, forms a chromatin-associated complex with TTC5/STRAP and p300/EP300 to stimulate HSR transcription, therefore increasing cell survival (PubMed:18451878). 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). Activates transcription of transcription factor FOXR1 which in turn activates transcription of the heat shock chaperones HSPA1A and HSPA6 and the antioxidant NADPH-dependent reductase DHRS2 (PubMed:34723967). Also serves 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). Also plays 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).
(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.
Phosphorylated (PubMed:10359787, PubMed:11583998, PubMed:26159920, PubMed:9499401). Phosphorylated in unstressed cells; this phosphorylation is constitutive and implicated in the repression of HSF1 transcriptional activity (PubMed:16278218, PubMed:8940068, PubMed:8946918, PubMed:9121459). 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:10747973, PubMed:12646186, PubMed:8940068, PubMed:8946918, PubMed:9121459, PubMed:9535852). 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).
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).
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).
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).
Belongs to the HSF family.
HSTF1, HSF1, Heat shock factor protein 1, HSF 1, Heat shock transcription factor 1, HSTF 1
Proteins
Oncology
57260Da
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