HSF-driven cytosolic heat shock response

The heat shock response couples proteotoxic stress to transcriptional induction of the cytosolic chaperone network. Its driver is heat shock factor (HSF), a winged helix-turn-helix transcription factor found across eukaryotes. HSF binds heat shock elements (HSEs), inverted nGAAn pentamer repeats, as a homotrimer and activates RNA polymerase II transcription of chaperone genes. How HSF is held in check differs between lineages. In metazoans, exemplified by human HSF1, HSF is kept as an inert monomer in complexes with HSP90 and HSP70. Proteotoxic stress titrates these chaperones away, and HSF1 then trimerizes, binds HSEs and concentrates in nuclear stress granules. The induced chaperones feed back to switch HSF1 off. In budding yeast, Hsf1 is constitutively trimeric and nuclear. Its essential job is to maintain basal expression of the Hsp70 and Hsp90 genes, and stress raises its activity further. The chaperone output falls into three activities. Hsp70 family foldases refold non-native clients by ATP-driven cycles. J-domain co-chaperones deliver clients and stimulate the Hsp70 ATPase, and HSP110- and BAG-family nucleotide-exchange factors reset the cycle. HSP90 is an ATP-dependent chaperone for metastable signaling and structural clients and is also the main repressor of metazoan HSF1. Small heat shock proteins are ATP-independent holdases that keep heat-denatured proteins soluble and refolding-competent for the ATP-dependent chaperones. Nematodes add an HSF-1/DAF-16-co-regulated branch of atypical 12-kDa small HSPs that contributes to longevity rather than to the acute response. In C. elegans the capacity of the response also falls sharply at the onset of reproduction, when repressive chromatin at stress loci blocks HSF-1 binding.

MODULE:heat_shock_responseDRAFTCONCRETEBiological Processmodules/heat_shock_response.yaml
cellular response to heatGO:0034605
PMID:7935471
Activation 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 structure.
Human HSF1 is an inactive monomer in unstressed cells and homotrimerizes to acquire HSE binding on heat stress.
Heat stress (39 to 42 degrees C) disrupts these interactions, and hHSF1 homotrimerizes and acquires heat shock element DNA-binding ability.
PMID:9727490
Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1.
HSP90 forms a stress-sensitive complex with human HSF1 and is a major repressor of its activation.
We conclude that Hsp90, by itself and/or associated with multichaperone complexes, is a major repressor of HSF1.
PMID:27320198
Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis.
The essential function of yeast Hsf1 is basal expression of Hsp70 and Hsp90; restoring it lets cells grow without Hsf1.
Strikingly, rescuing basal expression of Hsp70 and Hsp90 chaperones enabled robust cell growth in the complete absence of Hsf1.
PMID:15611166
The L-type cyclin CYL-1 and the heat-shock-factor HSF-1 are required for heat-shock-induced protein expression in Caenorhabditis elegans.
hsf-1 mutation virtually abolishes heat-shock-induced hsp-16.2 transcription, establishing HSF-1 as the inducing factor for heat shock genes in the worm.
Heat-shock-induced expression of hsp-16.2 mRNA was reduced in cyl-1 mutants and virtually eliminated in hsf-1 and sup-45 mutants, as compared to wild-type expression.
PMID:27688402
E2F coregulates an essential HSF developmental program that is distinct from the heat-shock response.
Heat shock relocates worm HSF-1 to distal HSEs of the hsc70 (hsp-1) and hsp90 promoters, which then drive their heat induction; the developmental HSF-1 program uses different sites and is outside this module.
In contrast to the results for development at 20°C, activity of the hsc70 and hsp90 promoters at 34°C is independent of the GC-rich motif or the proximal HSEs but is regulated entirely by the tandem distal HSEs
PMID:26212459
Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction.
In C. elegans the heat shock response collapses in early adulthood because repressive chromatin at stress loci prevents HSF-1 binding.
This results in a repressed chromatin state that interferes with HSF-1 binding and suppresses transcription initiation in response to stress.
PMID:14668486
Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones.
Molecular chaperones are transcriptional targets of HSF-1, and their individual knockdown has smaller effects than loss of HSF-1, consistent with a chaperone network output.
Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals.
file:genes/human/HSF1/HSF1-ai-review.yaml
human HSF1 gene review
Core function: stress-activated homotrimeric HSE-binding transcription activator (GO:0001228) in cellular response to heat; held as an inert monomer by HSP90, HSP70 and DNAJB1 complexes.
file:genes/yeast/HSF1/HSF1-ai-review.yaml
yeast HSF1 gene review
Core function: HSE-binding transcription activator (GO:0001228) driving basal and stress-induced Hsp70 and Hsp90 transcription; constitutively trimeric and largely nuclear, unlike metazoan HSF1.
file:genes/worm/hsf-1/hsf-1-ai-review.yaml
worm hsf-1 gene review
Accepts HSF-1 as the HSE-binding master transcription factor of the heat shock response; developmental, immune, autophagy and lifespan roles are kept as non-core.
file:projects/CAEEL_PROTEOSTASIS.md
C. elegans Proteostasis Network Project
Project page whose heat shock response and chaperone tier this module organizes for C. elegans.

History. This module was first curated as a C. elegans-only module (MODULE:c_elegans_heat_shock_response) and was generalized to the eukaryotic HSF-driven response. The worm evidence is kept; human and yeast exemplars were added from their gene reviews. C. elegans members remain among the representative members of every role. Boundary. The module covers HSF activation and HSE binding (part 1) and the cytosolic chaperone output it induces (parts 2 to 4), with an optional nematode-specific atypical sHSP branch (part 5). The context taxon is Eukaryota because HSF, Hsp70, HSP90 and the BAG and HSP110 exchange factors have PAINT nodes at or above Eukaryota (see ancestral_nodes). The representative members are opisthokont only (human, yeast, worm). The small HSP holdase node (PTN000897708) is placed at Eumetazoa, so yeast Hsp26/Hsp42 are not used as representatives. Excluded: heat-shock-independent HSF programs, such as the worm developmental program with EFL-1/DPL-1 (PMID:27688402), linker cell death through the ubiquitin-proteasome system (PMID:26952214) and autophagy induction after hormetic heat (PMID:28198373). HSF1 roles in mitosis, DNA repair and cancer are also excluded, as are the ER unfolded protein response and the mitochondrial UPR. HSF also induces the chaperonin CCT/TRiC, which is modeled separately in MODULE:cct_chaperonin_folding and is not repeated here. Activation mode as a variant set. Part 1 uses a variant set with the axis taxon / HSF activation mode. The metazoan variant is a latent monomer that trimerizes under stress and is repressed by HSP90 and HSP70 (human HSF1). Worm HSF-1 is placed in this variant by family membership and by its restraint at an early activation step by DDL-1/DDL-2. It differs from human HSF1 in two ways: it is constitutively nuclear (PMID:23107491), and a stress-triggered monomer-to-trimer switch has not been shown directly in the worm. The yeast variant is constitutively trimeric and nuclear, and its essential output is basal Hsp70/Hsp90 expression. The family-level MF is GO:0001228, as in the human and yeast reviews. The worm hsf-1 review asserts its parent GO:0003700. HSP90 feedback on HSF. HSP90 represses human HSF1 (PMID:9727490). This is modeled as a NEGATIVELY_REGULATES connection from the HSP90 part to HSF activation, with metazoan context. The human HSF1 review also lists HSP70/DNAJB1 complexes as repressors, and yeast Hsf1 is under Hsp70/Hsp90 feedback (yeast HSF1 review). These are recorded in prose only, because this module cites no verbatim quote for the HSP70 arm. No cached worm study tests whether HSP-90 binds or represses HSF-1, so the connection is not asserted for nematodes (see knowledge_gaps). Regulators kept as context. Worm DDL-1/DDL-2 hold HSF-1 inactive under insulin/IGF-1-like signaling (PMID:22265419). PQM-1 contributes to heat induction of worm hsp-90 (PMID:29949773). JMJD-3.1 and H3K27me3 set the reproductive decline of the worm response (PMID:26212459). None of these has a gene review, so they are not modeled as members. HSF1 post-translational modifications (phosphorylation, SUMOylation, acetylation) are likewise left to the HSF1 review. Hsp70 cofactors. The J-domain role is grounded by human DNAJB1 only. No worm Hsp40 (DNJ) gene has a review, and no cached paper names the HSF-1-induced worm Hsp40 partner. DNJ-13 (PMID:25053410) and DNJ-19 (PMID:19165329) are mentioned in text only. Human HSPH1 (HSP110) has no review and is not used, so worm HSP-110 is the only HSP110 representative. The HSPA1A review gives its core MF as the parent GO:0044183, while its description calls HSPA1A an ATP-dependent foldase. The family-level MF here is GO:0140662, as in the worm hsp-1, hsp-70 and F44E5.4 reviews. Small HSP holdases. GO has no current holdase term, because GO:0051082 was obsoleted. The worm hsp-16 reviews propose a holdase chaperone activity NTR, and the HSPB1 review now proposes the same NTR (its GO:0044183 rows are MODIFY to it). Until GO creates that term, the family-level function is the parent GO:0044183, and the holdase sense is described in prose. Atypical small HSPs. The 12-kDa sHSPs are a nematode-specific optional part that follows their gene reviews. HSP-12.3 forms tetramers and HSP-12.6 is monomeric; neither shows in vitro chaperone activity. Because hsp-12.6 is not stress-inducible, no heat-response process is asserted for it. Their link to HSF-1 runs through HSF-1/DAF-16 co-regulation of sHSP genes in reduced insulin signaling and longevity (PMID:12750521), not through acute heat induction. Relation to other modules. MODULE:bacterial_dnak_dnaj_refolding_cycle models the bacterial DnaK/DnaJ/GrpE Hsp70 cycle. Part 2 here is the eukaryotic cytosolic counterpart, with HSP110- and BAG-family NEFs in place of GrpE, inside a stress-induced transcriptional program, so the two modules do not duplicate each other. MODULE:cct_chaperonin_folding covers the CCT/TRiC chaperonin.

8Nodes
5Parts
1Variant Sets
2Variants
10Annotons
6Connections

Derived QC

Recommended-field compliance

81.8% recommended fields populated
  • knowledge_gaps[0] · provenance (0/1)
  • knowledge_gaps[1].provenance[0] · reference_section_type (0/1)

Module deep research

✗ none found

No MODULE:heat_shock_response deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

13 gene-function check(s) reflected in core functions · 0 conflict(s) · 15 evidence or coverage gap(s) (28 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
metazoan_hsf1_tf HSF1 (human)
UniProtKB:Q00613
Family Representative 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
metazoan_hsf1_tf HSF-1 (worm)
UniProtKB:G5EFT5
Family Representative 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
fungal_hsf1_tf Hsf1 (budding yeast)
UniProtKB:P10961
Family Representative 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsp70_foldase HSP-1 (worm Hsc70)
UniProtKB:P09446
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsp70_foldase HSP-70/C12C8.1 (worm, inducible)
UniProtKB:O45246
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsp70_foldase F44E5.4 (worm, inducible)
UniProtKB:G5ECU5
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsp70_foldase HSPA1A (human, inducible)
UniProtKB:P0DMV8
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
jdp_cochaperone DNAJB1 (human)
UniProtKB:P25685
Family Representative 		ATPase activator activity
GO:0001671 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsp110_nef HSP-110 (worm)
UniProtKB:Q05036
Family Representative 		adenyl-nucleotide exchange factor activity
GO:0000774 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bag_nef BAG-1 (worm)
UniProtKB:O44739
Family Representative 		adenyl-nucleotide exchange factor activity
GO:0000774 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bag_nef BAG1 (human)
UniProtKB:Q99933
Family Representative 		adenyl-nucleotide exchange factor activity
GO:0000774 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsp90_foldase HSP-90/DAF-21 (worm)
UniProtKB:Q18688
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsp90_foldase HSP90AA1 (human)
UniProtKB:P07900
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
shsp_holdase_activity HSP-16.1 (worm)
UniProtKB:P34696
Family Representative 		protein folding chaperone (ATP-independent holdase)
GO:0044183 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
shsp_holdase_activity HSP-16.2 (worm)
UniProtKB:P06582
Family Representative 		protein folding chaperone (ATP-independent holdase)
GO:0044183 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
shsp_holdase_activity HSP-16.41 (worm)
UniProtKB:P06581
Family Representative 		protein folding chaperone (ATP-independent holdase)
GO:0044183 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
shsp_holdase_activity HSP-16.48 (worm)
UniProtKB:P02513
Family Representative 		protein folding chaperone (ATP-independent holdase)
GO:0044183 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
shsp_holdase_activity HSPB1/Hsp27 (human)
UniProtKB:P04792
Family Representative 		protein folding chaperone (ATP-independent holdase)
GO:0044183 		Review Disagreement
The review removes, modifies, or marks this term over-annotated and provides no retained/core support. Review the rationale; rejection of an evidence row alone is not a biological NOT.
hsp12_3_shsp HSP-12.3
UniProtKB:Q20164
Gene 		heat shock protein binding
GO:0031072 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsp12_6_shsp HSP-12.6
UniProtKB:G5EE36
Gene 		identical protein binding
GO:0042802 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
metazoan_hsf1_tf Heat shock factor 1 (metazoan)
PANTHER:PTHR10015
Family 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10015.
fungal_hsf1_tf Heat shock factor (fungal Hsf1)
PANTHER:PTHR10015
Family 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10015.
hsp70_foldase Cytosolic Hsp70/Hsc70 chaperones
PANTHER:PTHR19375
Family 		ATP-dependent protein folding chaperone
GO:0140662 		Family Function Unreviewed
Family review leaves GO:0140662 UNRESOLVED. Canonical Hsp70/DnaK folding activity remains positive, including direct denatured-luciferase reactivation evidence for yeast Ssa1. A universal grant across this heterogeneous family is not justified. The current term requires ATP-driven assistance to protein folding; HscA ATPase stimulation, client capture and cluster transfer do not alone establish that endpoint. E. coli HscA stabilizes disordered IscU and has model-client antiaggregation activity. The full PMID9852006 study separately reports failure to restore denatured-luciferase activity in the tested Hsc66 partner combinations, with a positive DnaK control. Together these observations make generic folding assignments over-annotated for the E. coli target without proving impossibility for every substrate or transferring a negative experiment to the Pseudomonas and Azotobacter homologs. Their folding endpoints remain unresolved. The negative Hsp110 judgment for HSPH1/Q92598 remains: it acts as a nucleotide-exchange factor and holdase rather than an independent ATP-driven folding chaperone. The exact former exception object is archived because live member exceptions cannot qualify an UNRESOLVED universal scope; no negative HscA exception, loss event or new broad ATPase grant is added. HSPA13 and other divergent proteins remain member-level questions.
jdp_cochaperone Class B J-domain proteins (DNAJB1-type Hsp40)
Family 		ATPase activator activity
GO:0001671 		Family Id Missing
The family has no identifier linking it to a curated family review.
hsp110_nef HSP110/HSPH nucleotide-exchange factors
PANTHER:PTHR45639
Family 		adenyl-nucleotide exchange factor activity
GO:0000774 		Family Function Unreviewed
Family review leaves GO:0000774 UNRESOLVED. HSPA4/Apg2 in SF6 supports nucleotide-exchange activity. HSPH1, LHS1/GRP170 and other Hsp110-related branches also have nucleotide-exchange evidence, so the HSPA4 branch is not the only applicable group. The complete boundary among the diverse family members remains unresolved. HSPA4 must be distinguished from conventional Hsp70 substrate-cycling proteins and ribosome-associated chaperones. Nucleotide exchange, substrate binding, ATP hydrolysis and membership in a particular folding complex are separate claims, and none follows solely from an Hsp70-family name.
bag_nef BAG-domain co-chaperones (BAG1 type)
PANTHER:PTHR12329
Family 		adenyl-nucleotide exchange factor activity
GO:0000774 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR12329.
hsp90_foldase Cytosolic HSP90 chaperones
PANTHER:PTHR11528
Family 		ATP-dependent protein folding chaperone
GO:0140662 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11528.
shsp_holdase_activity Canonical small heat shock proteins (alpha-crystallin domain)
PANTHER:PTHR45640
Family 		protein folding chaperone (ATP-independent holdase)
GO:0044183 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR45640.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • hsp90_chaperone ⊣ hsf_activation [closed]
    hsp90_chaperone is regulated by hsf_activation: feedback loop closed

Gene-review completeness (20/20 grounded genes reviewed)

15 complete review(s) · 17 with deep research · 0 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
bag-1 O44739 ✓ ✓ ✓
BAG1 Q99933 ✓ 37/38 ✓
DNAJB1 P25685 ✓ 64/70 ✓
F44E5.4 G5ECU5 ✓ ✓ ✓
hsf-1 G5EFT5 ✓ 60/61 ✓
HSF1 P10961 ✓ ✓ ✓
HSF1 Q00613 ✓ ✓ ✗
hsp-1 P09446 ✓ ✓ ✓
hsp-110 Q05036 ✓ ✓ ✓
hsp-12.3 Q20164 ✓ ✓ ✓
hsp-12.6 G5EE36 ✓ ✓ ✓
hsp-16.1 P34696 ✓ ✓ ✓
hsp-16.2 P06582 ✓ ✓ ✓
hsp-16.41 P06581 ✓ ✓ ✓
hsp-16.48 P02513 ✓ ✓ ✓
hsp-70 O45246 ✓ ✓ ✓
hsp-90 Q18688 ✓ ✓ ✓
HSP90AA1 P07900 ✓ 506/522 ✗
HSPA1A P0DMV8 ✓ 195/197 ✓
HSPB1 P04792 ✓ ✓ ✗

Details

Context
EukaryotaNCBITaxon:2759
heat shock or other proteotoxic stress
HSF-driven cytosolic heat shock responseBiological Processheat_shock_response

HSF activation and HSE-dependent transcription (latent-monomer metazoan or constitutively trimeric yeast mode). The cytosolic chaperone network it induces: the Hsp70 foldase cycle with J-domain co-chaperones and HSP110- and BAG-family nucleotide-exchange factors, the HSP90 chaperone (also the HSF1 repressor in metazoa), small HSP holdases, and a nematode-specific HSF-1/DAF-16-co-regulated atypical sHSP branch.

cellular response to heatGO:0034605
Context
EukaryotaNCBITaxon:2759
heat shock or other proteotoxic stress

Connections

hsf_activation -> hsp70_folding_cycle Positively Regulates
HSF drives Hsp70 transcription through HSEs. Worm HSF-1 binds the distal HSEs of hsp-1 during heat shock. In yeast, basal Hsp70 (SSA2) expression is one of the two essential Hsf1 outputs.
PMID:27688402
E2F coregulates an essential HSF developmental program that is distinct from the heat-shock response.
Heat-induced worm hsc70 promoter activity depends on distal HSEs.
activity of the hsc70 and hsp90 promoters at 34°C is independent of the GC-rich motif or the proximal HSEs but is regulated entirely by the tandem distal HSEs
PMID:27320198
Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis.
Basal Hsp70 and Hsp90 expression is the essential output of yeast Hsf1.
Strikingly, rescuing basal expression of Hsp70 and Hsp90 chaperones enabled robust cell growth in the complete absence of Hsf1.
hsf_activation -> hsp90_chaperone Positively Regulates
HSF drives HSP90 transcription. Worm HSF-1 induces hsp-90 through distal HSEs, with a PQM-1 contribution. Yeast Hsf1 maintains basal HSC82 expression.
hsp90_chaperone -> hsf_activation Negatively Regulates
Negative feedback. HSP90, alone or in multichaperone complexes, binds latent human HSF1 and represses its activation. The complex dissociates under stress, when non-native proteins compete for HSP90. Asserted for metazoa on human evidence; not tested in C. elegans (see knowledge_gaps).
Context
MetazoaNCBITaxon:33208
PMID:9727490
Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1.
Lowering HSP90, but not HSP70 or other co-chaperones, activates human HSF1, and HSP90 is a major HSF1 repressor.
Reduction of the level of Hsp90 but not of Hsp/c70, Hop, Hip, p23, CyP40, or Hsp40 dramatically activates HSF1.
file:genes/human/HSP90AA1/HSP90AA1-ai-review.yaml
human HSP90AA1 gene review
Records that HSP90 binding to HSF1 represses the heat shock response.
hsf_activation -> shsp_holdase Positively Regulates
HSF is required for heat-induced small HSP transcription (worm hsp-16.2 and hsp-16.41).
hsf_activation -> atypical_shsp_output Positively Regulates
Nematode branch: HSF-1 with DAF-16 activates sHSP genes in reduced insulin signaling. Whether HSF-1 binds the 12-kDa sHSP promoters directly has not been shown in the cached literature.
Context
NematodaNCBITaxon:6231
shsp_holdase -> hsp70_folding_cycle Provides Input For
Holdase-bound, refolding-competent clients are handed to the ATP-dependent chaperones.
PMID:20178975
Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-Tooth neuropathy.
sHSP-client complexes are later cleared by the ATP-dependent heat shock proteins.
These sHSP-unfolded protein complexes act as repositories that are later cleared out by the ATP-dependent heat shock proteins
Part 1: stress-regulated heat shock factor binding HSEs and inducing chaperone genes
HSF activation and HSE-dependent transcriptionRegulatory Stephsf_activation

HSF binds HSEs (continuous inverted nGAAn pentamers) as a trimer and activates RNA polymerase II transcription of chaperone genes. The lineages differ in how HSF is kept inactive and how stress activates it (variant set). In metazoans, HSF1 is a latent monomer that trimerizes when stress titrates away its HSP90/HSP70 repressors. In budding yeast, Hsf1 is constitutively trimeric and nuclear and drives essential basal chaperone expression. Heat shock concentrates HSF in nuclear stress granules in both human and worm cells.

Variant set: HSF activation mode by taxon / HSF activation mode (Exactly One)

Metazoan latent-monomer HSF1 (human; worm HSF-1 by family and pathway context) versus constitutively trimeric, nuclear fungal Hsf1 (budding yeast). Both are HSF family members (PTHR10015) that descend from the eukaryotic PAINT node PTN007416549.

Metazoan latent-monomer HSF1, repressed by HSP90/HSP70Regulatory Stepmetazoan_latent_monomer_hsf

In unstressed cells, HSF1 is an inert monomer, held by intramolecular leucine-zipper contacts and by HSP90- and HSP70-containing complexes. Proteotoxic stress releases it. HSF1 then homotrimerizes, gains HSE binding, accumulates in nuclear stress granules and activates HSP70, HSP90 and small HSP genes. The induced chaperones attenuate it again. Worm HSF-1 belongs here by family and by an early activation step that DDL-1/DDL-2 restrain under insulin/IGF-1-like signaling. Unlike human HSF1, worm HSF-1 is constitutively nuclear, and its trimerization switch is inferred rather than shown.

Context
MetazoaNCBITaxon:33208

Annotons

Metazoan HSF1 HSE-binding transcription activator
metazoan_hsf1_tf
Participant: Family: Heat shock factor 1 (metazoan)
Family:
Heat shock factor 1 (metazoan)PANTHER:PTHR10015
Representative Members: HSF1 (human)UniProtKB:Q00613 HSF-1 (worm)UniProtKB:G5EFT5

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228
Targets: HSE-containing promoters of HSP70, HSP90 and small HSP genes

Processes

cellular response to heatGO:0034605 positive regulation of transcription by RNA polymerase IIGO:0045944

Locations

nucleusGO:0005634

Stress-activated master transcription factor; a latent monomer that homotrimerizes to bind HSEs and induce chaperone genes.

PMID:7935471
Activation 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 structure.
Human HSF1 is monomeric and inactive in unstressed cells and trimerizes to bind HSEs on heat stress.
In unstressed human cells (37 degrees C), hHSF1 appears to be in an inactive, monomeric state that may be maintained through intramolecular interactions stabilized by transient interaction with hsp70.
PMID:9727490
Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1.
An HSP90-containing HSF1 complex exists in unstressed cells and dissociates during stress.
Hsp90-containing HSF1 complex is present in the unstressed cell and dissociates during stress.
PMID:21510947
Diversity in DNA recognition by heat shock transcription factors (HSFs) from model organisms.
Worm HSF-1 binds continuous nGAAn HSEs but, unusually, not discontinuous ones.
Among these, only C. elegans HSF failed to bind the discontinuous nGAAn units
PMID:23107491
Caenorhabditis elegans HSF-1 is an essential nuclear protein that forms stress granule-like structures following heat shock.
Heat shock redistributes worm HSF-1 into nuclear stress granules that mark active transcription, dependent on DNA binding.
Rapid formation of HSF-1 stress granules required HSF-1 DNA-binding activity
PMID:22265419
HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity.
Insulin/IGF-1-like signaling regulates an early step of worm HSF-1 activation via DDL-1 and DDL-2.
This regulation occurs at an early step of HSF-1 activation via two HSF-1 regulators, DDL-1 and DDL-2.
file:genes/human/HSF1/HSF1-ai-review.yaml
human HSF1 gene review
Core functions: GO:0001228 transcription activator in cellular response to heat, and HSE binding (GO:0000978) by HSF1 trimers.
file:genes/worm/hsf-1/hsf-1-ai-review.yaml
worm hsf-1 gene review
Core functions: DNA-binding transcription factor activity (GO:0003700), sequence-specific HSE binding and homo-oligomerization.
Constitutively trimeric, nuclear fungal Hsf1Regulatory Stepfungal_constitutive_trimer_hsf

Budding yeast Hsf1 is the single, essential HSF. It is constitutively trimeric and nuclear. Its essential function under all conditions is basal transcription of a compact set of chaperone genes; restoring basal Hsp70 (SSA2) and Hsp90 (HSC82) expression alone lets cells grow without Hsf1. Heat and proteotoxic stress raise its activity through phosphorylation and release from Hsp70/Hsp90 feedback, and it then drives chaperone induction for thermotolerance.

Context
FungiNCBITaxon:4751

Annotons

Yeast Hsf1 constitutive HSE-binding transcription activator
fungal_hsf1_tf
Participant: Family: Heat shock factor (fungal Hsf1)
Family:
Heat shock factor (fungal Hsf1)PANTHER:PTHR10015
Representative Members: Hsf1 (budding yeast)UniProtKB:P10961

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228
Targets: HSE-containing promoters of Hsp70 (SSA) and Hsp90 (HSC82, HSP82) genes

Processes

cellular response to heatGO:0034605 positive regulation of transcription by RNA polymerase IIGO:0045944

Locations

nucleusGO:0005634

Constitutively trimeric, nuclear HSF whose essential output is basal Hsp70/Hsp90 expression; stress raises its activity further.

PMID:18270585
Hsf1 activation inhibits rapamycin resistance and TOR signaling in yeast revealed by combined proteomic and genetic analysis.
Yeast Hsf1 binds HSEs as a homotrimer.
Hsf1 forms a homotrimer and recognizes heat shock elements (HSEs) in promoters of target genes consisting of at least three inverted repeats of nGAAn.
PMID:27320198
Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis.
Yeast Hsf1 is constitutively nuclear and essential; mammalian HSF1 instead is repressed and dispensable without stress.
Hsf1 is constitutively nuclear and essential for yeast growth under all conditions
PMID:27320198
Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis.
Of the synthetic Hsf1 target genes, only the Hsp70 SSA2 and Hsp90 HSC82 genes are indispensable for bypassing Hsf1.
we found that that only SSA2 and HSC82 were indispensable for Hsf1 bypass
file:genes/yeast/HSF1/HSF1-ai-review.yaml
yeast HSF1 gene review
Core function: GO:0001228 transcription activator for basal and stress-induced chaperone gene expression.
Part 2: ATP-dependent Hsp70 refolding of heat-denatured clients with J-domain and nucleotide-exchange cofactors
Cytosolic Hsp70 folding cycle with J-domain, HSP110 and BAG cofactorsBiological Processhsp70_folding_cycle

Cytosolic Hsp70s bind non-native clients and refold them through ATP hydrolysis-coupled cycles. Constitutive Hsc70 (worm HSP-1) is abundant without stress and modestly heat-inducible. The inducible HSP70s (worm HSP-70/C12C8.1 and F44E5.4; human HSPA1A) are strongly HSF-dependent. J-domain co-chaperones (human DNAJB1) deliver clients and stimulate the Hsp70 ATPase. HSP110-family (worm HSP-110) and BAG-domain (worm BAG-1, human BAG1) nucleotide-exchange factors release ADP to reset the cycle.

protein foldingGO:0006457

Annotons

Cytosolic Hsp70 ATP-dependent foldase
hsp70_foldase
Participant: Family: Cytosolic Hsp70/Hsc70 chaperones
Family:
Cytosolic Hsp70/Hsc70 chaperonesPANTHER:PTHR19375
Representative Members: HSP-1 (worm Hsc70)UniProtKB:P09446 HSP-70/C12C8.1 (worm, inducible)UniProtKB:O45246 F44E5.4 (worm, inducible)UniProtKB:G5ECU5 HSPA1A (human, inducible)UniProtKB:P0DMV8

Function

ATP-dependent protein folding chaperoneGO:0140662
Substrates: heat-denatured or misfolded cytosolic protein

Processes

protein foldingGO:0006457

Locations

cytosolGO:0005829

ATP-driven client refolding by constitutive Hsc70 and the strongly heat-inducible HSP70s.

PMID:2841196
The Caenorhabditis elegans hsp70 gene family: a molecular genetic characterization.
Worm hsp70A (hsp-1) is abundant without stress and heat-inducible.
Transcripts of another gene, hsp70A, are abundant in control worms and are also increased (two- to six-fold) upon heat shock.
PMID:27688402
E2F coregulates an essential HSF developmental program that is distinct from the heat-shock response.
Heat induction of the worm inducible hsp-70 (C12C8.1) almost entirely requires HSF-1.
The expression of classical heat-shock genes hsp-16.41 and hsp-70 (C12C8.1) was severely compromised (>99% reduced) in hsf-1(ok600) animals exposed to heat shock compared with N2 animals
PMID:25053410
The balanced regulation of Hsc70 by DNJ-13 and UNC-23 is required for muscle functionality.
Worm Hsc70 folds non-native proteins with J-domain and BAG-domain cofactors.
The molecular chaperone Hsc70 assists in the folding of non-native proteins together with its J domain- and BAG domain-containing cofactors.
PMID:21231916
The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities.
Human HSPA1A protects cells from heat-induced death.
overexpression of HSPA1A protected cells from heat-induced cell death
file:genes/worm/hsp-1/hsp-1-ai-review.yaml
worm hsp-1 gene review
Core function: ATP-dependent protein folding chaperone (GO:0140662).
file:genes/worm/hsp-70/hsp-70-ai-review.yaml
worm hsp-70 gene review
Core function: heat-inducible cytosolic ATP-dependent folding chaperone (GO:0140662) in protein refolding and response to heat.
file:genes/worm/F44E5.4/F44E5.4-ai-review.yaml
worm F44E5.4 gene review
Core function: stress-inducible cytosolic ATP-dependent folding chaperone (GO:0140662), inferred from family membership.
file:genes/human/HSPA1A/HSPA1A-ai-review.yaml
human HSPA1A gene review
Core function: major stress-inducible HSP70 acting as an ATP-dependent foldase in protein refolding and cellular heat acclimation (MF given as GO:0044183).
Class B J-domain co-chaperone stimulating the Hsp70 ATPase
jdp_cochaperone
Participant: Family: Class B J-domain proteins (DNAJB1-type Hsp40)
Family:
Class B J-domain proteins (DNAJB1-type Hsp40) No PANTHER family id is asserted. The DNAJB1 PANTHER family (PTHR24078) is a large, heterogeneous J-domain family, and no worm member has a review.
Representative Members: DNAJB1 (human)UniProtKB:P25685

Function

ATPase activator activityGO:0001671
Targets: Hsp70 nucleotide-binding domain (via the J-domain HPD motif)

Processes

protein foldingGO:0006457

Locations

cytosolGO:0005829

Binds non-native clients, delivers them to Hsp70 and stimulates its ATPase through the J-domain.

PMID:24318877
Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro.
DNAJB1 and other J proteins, combined with Hsp70-NEF pairs, set Hsp70 ATPase and luciferase refolding activity.
we combined the Hsp70-NEF pairs with cochaperones of the J protein family (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations
file:genes/human/DNAJB1/DNAJB1-ai-review.yaml
human DNAJB1 gene review
Core functions: protein folding chaperone (GO:0044183) and ATPase activator activity (GO:0001671) for HSP70.
HSP110-family Hsp70 nucleotide-exchange factor
hsp110_nef
Participant: Family: HSP110/HSPH nucleotide-exchange factors
Family:
HSP110/HSPH nucleotide-exchange factorsPANTHER:PTHR45639
Representative Members: HSP-110 (worm)UniProtKB:Q05036

Function

adenyl-nucleotide exchange factor activityGO:0000774
Targets: Hsp70 nucleotide-binding domain

Processes

protein foldingGO:0006457

Locations

cytosolGO:0005829

HSP110-family nucleotide-exchange factor that releases ADP from Hsp70; also limits aggregation of misfolding-prone proteins.

PMID:19165329
An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans.
Knockdown of hsp-110 (C30C11.4), with other chaperones, increases aggregation of misfolded SOD1 in worm neurons.
hits of a collective of chaperone components registered strong increases of aggregation, including an Hsp110 (C30C11.4), a DnaJ (A2) (dnj-19), an Hsp70 (stc-1), and a neuron specific Hsp16 (F08H9.4)
PMID:16688211
Chaperone network in the yeast cytosol: Hsp110 is revealed as an Hsp70 nucleotide exchange factor.
Family-level grounding: HSP110 (yeast Sse1) is an Hsp70 nucleotide-exchange factor.
acts as an efficient nucleotide exchange factor (NEF) for both yeast cytosolic Hsp70s, Ssa1p and Ssb1p
file:genes/worm/hsp-110/hsp-110-ai-review.yaml
worm hsp-110 gene review
Core function: adenyl-nucleotide exchange factor activity (GO:0000774) for Hsp70 in the cytosol.
BAG-domain Hsp70 nucleotide-exchange factor
bag_nef
Participant: Family: BAG-domain co-chaperones (BAG1 type)
Family:
BAG-domain co-chaperones (BAG1 type)PANTHER:PTHR12329
Representative Members: BAG-1 (worm)UniProtKB:O44739 BAG1 (human)UniProtKB:Q99933

Function

adenyl-nucleotide exchange factor activityGO:0000774
Targets: Hsp70/Hsc70 ATPase domain

Processes

protein foldingGO:0006457

Locations

cytosolGO:0005829

BAG-domain co-chaperone that stimulates the Hsp70 ATPase cycle and client release; tunes rather than drives folding, and can antagonize it in excess.

PMID:25053410
The balanced regulation of Hsc70 by DNJ-13 and UNC-23 is required for muscle functionality.
Worm BAG-1 stimulates the Hsc70 ATPase with higher affinity than the BAG-domain fragments of UNC-23.
C-terminal fragments of UNC-23 instead perform all Hsc70-related functions, like ATPase stimulation and regulation of folding activity, albeit with lower affinity than BAG-1.
PMID:24318877
Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro.
BAG-domain proteins act as Hsp70 nucleotide-exchange factors.
Proteins with Bcl2-associated anthanogene (BAG) domains act as nucleotide exchange factors (NEFs) for the molecular chaperone heat shock protein 70
file:genes/worm/bag-1/bag-1-ai-review.yaml
worm bag-1 gene review
Core function: adenyl-nucleotide exchange factor activity (GO:0000774) for cytosolic Hsc70 HSP-1.
file:genes/human/BAG1/BAG1-ai-review.yaml
human BAG1 gene review
Core function: adenyl-nucleotide exchange factor activity (GO:0000774) for Hsp70/Hsc70.
Part 2: heat-inducible ATP-dependent HSP90 chaperone and metazoan HSF1 repressor
Cytosolic HSP90 ATP-dependent chaperoneMolecular Functionhsp90_chaperone

Cytosolic HSP90 is an ATP-dependent clamp chaperone. Co-chaperones regulate its cycle, which completes the maturation and stabilization of metastable clients such as kinases, steroid receptors and transcription factors. HSF induces it through HSEs: worm HSP-90 (historical mutant name DAF-21), the only cytosolic HSP90 in C. elegans, is induced through distal HSEs bound by HSF-1, with a PQM-1 contribution. In human cells, HSP90 is also the main repressor of HSF1, which closes the negative feedback loop of the response.

Annotons

HSP90 ATP-dependent chaperone
hsp90_foldase
Participant: Family: Cytosolic HSP90 chaperones
Family:
Cytosolic HSP90 chaperonesPANTHER:PTHR11528 PTHR11528 also contains the ER (GRP94) and mitochondrial (TRAP1) paralogs. The cytosolic clade is fixed by the PAINT node below. PANTHER places both representatives in PTHR11528:SF87, named after vertebrate HSP90-alpha, so the family level is kept.
Representative Members: HSP-90/DAF-21 (worm)UniProtKB:Q18688 HSP90AA1 (human)UniProtKB:P07900

Function

ATP-dependent protein folding chaperoneGO:0140662
Substrates: client proteins (kinases, steroid receptors, guanylyl cyclases, myosin)

Processes

protein foldingGO:0006457

Locations

cytosolGO:0005829

Heat-induced chaperone for client maturation and maintenance; in metazoa also binds and represses HSF1.

PMID:29949773
A PQM-1-Mediated Response Triggers Transcellular Chaperone Signaling and Regulates Organismal Proteostasis.
Worm hsp-90 expression depends partly on hsf-1 and its heat induction also needs PQM-1.
After HS treatment, hsp-90 was weakly induced in the hsf-1(sy441) mutant, albeit starting at a 50% lower basal expression level
PMID:21980476
Downregulation of the Hsp90 system causes defects in muscle cells of Caenorhabditis elegans.
Worm HSP-90 maintains myosin MYO-3 folding state in muscle.
aggregates of the myosin MYO-3 are visible in muscle cells, if DAF-21 is depleted
PMID:27339980
Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase.
Human HSP90 traps and stabilizes partially unfolded kinase clients.
Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase
file:genes/worm/hsp-90/hsp-90-ai-review.yaml
worm hsp-90 gene review
Core function: ATP-dependent protein folding chaperone (GO:0140662).
file:genes/human/HSP90AA1/HSP90AA1-ai-review.yaml
human HSP90AA1 gene review
Core function: ATP-dependent protein folding chaperone (GO:0140662) in the cytosol, through a co-chaperone-regulated ATPase cycle; its binding to HSF1 represses the heat shock response.
Part 2: ATP-independent small HSP holdase output
Small HSP holdasesMolecular Functionshsp_holdase

Canonical small heat shock proteins are alpha-crystallin-domain proteins that form dynamic oligomers. Without ATP, they bind heat-denatured proteins and keep them soluble and refolding-competent; the ATP-dependent chaperones later refold these clients. They do not refold clients themselves. The four worm hsp-16 genes (hsp-16.1, hsp-16.2, hsp-16.41, hsp-16.48) are arranged as divergently transcribed pairs sharing intergenic HSEs, are silent without stress and strictly HSF-1-dependent for heat induction. Human HSPB1 (Hsp27) is the vertebrate exemplar. GO has no current holdase term (see notes).

Annotons

Small HSP ATP-independent holdase
shsp_holdase_activity
Participant: Family: Canonical small heat shock proteins (alpha-crystallin domain)
Family:
Canonical small heat shock proteins (alpha-crystallin domain)PANTHER:PTHR45640
Representative Members: HSP-16.1 (worm)UniProtKB:P34696 HSP-16.2 (worm)UniProtKB:P06582 HSP-16.41 (worm)UniProtKB:P06581 HSP-16.48 (worm)UniProtKB:P02513 HSPB1/Hsp27 (human)UniProtKB:P04792

Function

protein folding chaperone (ATP-independent holdase)GO:0044183 Holdase sense. The worm hsp-16 and human HSPB1 reviews propose a holdase chaperone activity NTR; the parent GO:0044183 is used here until GO creates it.
Substrates: heat-denatured aggregation-prone protein

Processes

response to heatGO:0009408

Locations

cytoplasmGO:0005737

Heat-inducible sHSP holdase that prevents aggregation of denatured proteins and hands them on for ATP-dependent refolding; does not refold them itself.

PMID:1550963
Temporal and spatial expression patterns of the small heat shock (hsp16) genes in transgenic Caenorhabditis elegans.
Worm hsp16 transcription is entirely heat-shock dependent.
Transcription of the hsp16-lacZ transgenes was totally heat-shock dependent
PMID:15611166
The L-type cyclin CYL-1 and the heat-shock-factor HSF-1 are required for heat-shock-induced protein expression in Caenorhabditis elegans.
Worm hsp-16.2 heat induction requires HSF-1.
Heat-shock-induced expression of hsp-16.2 mRNA was reduced in cyl-1 mutants and virtually eliminated in hsf-1 and sup-45 mutants
PMID:27688402
E2F coregulates an essential HSF developmental program that is distinct from the heat-shock response.
Worm hsp-16.41 heat induction almost entirely requires HSF-1.
The expression of classical heat-shock genes hsp-16.41 and hsp-70 (C12C8.1) was severely compromised (>99% reduced) in hsf-1(ok600) animals exposed to heat shock compared with N2 animals
PMID:20178975
Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-Tooth neuropathy.
sHSPs such as HSPB1 cannot refold clients themselves but keep them folding-competent for the ATP-dependent chaperones.
However, they are able to bind unfolded substrates and keep them in a folding-competent state. These sHSP-unfolded protein complexes act as repositories that are later cleared out by the ATP-dependent heat shock proteins
file:genes/worm/hsp-16.2/hsp-16.2-ai-review.yaml
worm hsp-16.2 gene review
Core function: ATP-independent holdase in response to heat; protein refolding removed and GO:0051082 replaced by a holdase NTR.
file:genes/worm/hsp-16.1/hsp-16.1-ai-review.yaml
worm hsp-16.1 gene review
Core function: heat-inducible ATP-independent holdase (proposed holdase chaperone activity) in response to heat.
file:genes/worm/hsp-16.41/hsp-16.41-ai-review.yaml
worm hsp-16.41 gene review
Core function: heat-inducible ATP-independent holdase of the HSP-16 family (proposed holdase chaperone activity).
file:genes/worm/hsp-16.48/hsp-16.48-ai-review.yaml
worm hsp-16.48 gene review
Core function: heat-inducible ATP-independent holdase of the HSP-16 family (proposed holdase chaperone activity).
file:genes/human/HSPB1/HSPB1-ai-review.yaml
human HSPB1 gene review
Core function: ATP-independent sHSP holdase (proposed holdase chaperone activity NTR) that keeps non-native proteins refolding-competent during heat stress.
Part 3: nematode-specific HSF-1/DAF-16-co-regulated atypical 12-kDa sHSPs (longevity branch, not required for the acute response) (optional)
Nematode atypical 12-kDa small HSPs HSP-12.3 and HSP-12.6Biological Processatypical_shsp_output

The four 12-kDa sHSPs of C. elegans are essentially bare alpha-crystallin domains with very short N-terminal regions and no C-terminal tail. HSP-12.3 forms tetramers (with HSP-12.2) and HSP-12.6 is monomeric; neither has in vitro chaperone activity, and hsp-12.6 is not stress-inducible. HSF-1 and DAF-16 jointly activate sHSP genes when insulin/IGF-1 signaling is reduced, and this is how these genes connect to HSF-1. The branch contributes to longevity and delays polyglutamine aggregation. No holdase or heat-response function is asserted for HSP-12.6.

determination of adult lifespanGO:0008340
Context
NematodaNCBITaxon:6231
PMID:12750521
Regulation of aging and age-related disease by DAF-16 and heat-shock factor.
HSF-1 and DAF-16 together activate small heat shock protein genes that promote longevity and delay polyQ aggregation.
HSF-1 and DAF-16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity.

Annotons

HSP-12.3 tetrameric atypical sHSP
hsp12_3_shsp
Participant: Gene Product: HSP-12.3
Gene Product:
HSP-12.3UniProtKB:Q20164

Function

heat shock protein bindingGO:0031072
Targets: HSP-12.2

Processes

response to heatGO:0009408

Locations

cytoplasmGO:0005737

Atypical sHSP that associates with HSP-12.2 into tetramers but lacks in vitro chaperone activity.

PMID:9744800
Caenorhabditis elegans small heat-shock proteins Hsp12.2 and Hsp12.3 form tetramers and have no chaperone-like activity.
HSP-12.2 and HSP-12.3 are tetramers devoid of in vitro chaperone activity.
Exceptionally, too, both appear devoid of in vitro chaperone-like abilities.
file:genes/worm/hsp-12.3/hsp-12.3-ai-review.yaml
worm hsp-12.3 gene review
Core function: heat shock protein binding (GO:0031072) with response to heat; protein refolding removed.
HSP-12.6 monomeric atypical sHSP
hsp12_6_shsp
Participant: Gene Product: HSP-12.6
Gene Product:
HSP-12.6UniProtKB:G5EE36

Function

identical protein bindingGO:0042802

Locations

cytoplasmGO:0005737

Non-inducible, non-chaperone sHSP; included as an HSF-1/DAF-16 longevity-branch sHSP, not as an acute heat-response effector.

PMID:9139746
Unique structural features of a novel class of small heat shock proteins.
HSP-12.6 is not stress-inducible and does not prevent thermal aggregation in vitro.
Expression of HSP12.6 is limited to the first larval stage of C. elegans and is not significantly up-regulated by a wide range of stressors.
file:genes/worm/hsp-12.6/hsp-12.6-ai-review.yaml
worm hsp-12.6 gene review
Core function: identical protein binding (GO:0042802); response to heat marked as over-annotated.