HSPB8

UniProt ID: Q9UJY1
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

HSPB8 (heat shock protein beta-8, also called HSP22, H11 kinase, E2IG1 or alpha-crystallin C chain) is a member of the small heat shock protein (sHSP / HSP20, alpha-crystallin domain) family, predominantly expressed in skeletal muscle and heart. It is an ATP-independent molecular chaperone (holdase) that binds aggregation-prone and stress-destabilized client proteins. Its central role is in chaperone-assisted selective autophagy (CASA), where together with the co-chaperone BAG3, the Hsp70 chaperones HSPA8/HSC70 and HSPA1A, and the ubiquitin ligase STUB1/CHIP, HSPB8 routes damaged clients (e.g. filamin and polyglutamine-expanded proteins) for autophagic degradation via p62/SQSTM1, a process essential for maintenance of the muscle Z-disk under mechanical stress. HSPB8 forms homodimers and hetero-oligomers with other small HSPs (HSPB1, HSPB2, HSPB7) and DNAJB6. Despite an early report of protein kinase activity, recombinant HSPB8 lacks detectable kinase activity. It localizes to the cytoplasm and nucleus and translocates to nuclear foci during heat shock. Dominant variants (notably at the K141 hot spot) cause distal hereditary motor neuropathy, Charcot-Marie-Tooth disease type 2L, and myofibrillar/rimmed-vacuole myopathy.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005634 nucleus
IBA
GO_REF:0000033 		ACCEPT
Summary: Nuclear localization inferred phylogenetically; HSPB8 is directly documented in the nucleus and translocates to nuclear foci during heat shock.
Reason: Corroborated by direct experimental (IDA) evidence (PMID:19464326) and the UniProt subcellular-location record.
Supporting Evidence:
file:human/HSPB8/HSPB8-uniprot.txt
Nucleus {ECO:0000269|PubMed:19464326}
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		ACCEPT
Summary: Cytoplasmic localization inferred phylogenetically; the cytoplasm is the principal site where HSPB8 acts in CASA and as a holdase.
Reason: Corroborated by direct experimental (IDA) evidence (PMID:19464326, PMID:28144995) and the UniProt subcellular-location record.
Supporting Evidence:
file:human/HSPB8/HSPB8-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0034620 cellular response to unfolded protein
IBA
GO_REF:0000033 		ACCEPT
Summary: As a stress-inducible small HSP holdase, HSPB8 participates in the cellular response to unfolded protein. Supported by family inference and by direct functional data.
Reason: Phylogenetic inference is consistent with experimental evidence that HSPB8 prevents aggregation of unfolded/aggregation-prone clients and is induced by stress.
Supporting Evidence:
PMID:14985082
Hsp22 effectively prevents heat-induced aggregation of yeast alcohol dehydrogenase and bovine liver rhodanese
GO:0101031 protein folding chaperone complex
IBA
GO_REF:0000033 		ACCEPT
Summary: HSPB8 is a component of multi-chaperone complexes (the CASA complex with BAG3/HSPA8/STUB1, and sHSP hetero-oligomers). Membership in a protein-folding chaperone complex is well supported.
Reason: Direct experimental evidence places HSPB8 in the CASA complex and in ternary complexes with BAG3 and Hsp70, consistent with this phylogenetic annotation.
Supporting Evidence:
file:human/HSPB8/HSPB8-uniprot.txt
Component of the chaperone-assisted selective autophagy (CASA) complex consisting of BAG3, HSPA8/HSC70, HSPB8 and STUB1/CHIP
GO:0005634 nucleus
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic annotation of nuclear localization, consistent with the IBA and IDA nucleus annotations.
Reason: Agrees with stronger experimental evidence (PMID:19464326) placing HSPB8 in the nucleus.
Supporting Evidence:
file:human/HSPB8/HSPB8-uniprot.txt
Nucleus {ECO:0000269|PubMed:19464326}
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic annotation of cytoplasmic localization, redundant with the IBA and IDA cytoplasm annotations.
Reason: Correct compartment, agreeing with stronger experimental evidence.
Supporting Evidence:
file:human/HSPB8/HSPB8-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0034620 cellular response to unfolded protein
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based electronic annotation to the cellular response to unfolded protein, consistent with HSPB8's sHSP holdase function.
Reason: Redundant with the IBA and IMP annotations of the same process, all supported by HSPB8's documented anti-aggregation chaperone activity.
Supporting Evidence:
PMID:14985082
Hsp22 effectively prevents heat-induced aggregation of yeast alcohol dehydrogenase and bovine liver rhodanese
GO:0042803 protein homodimerization activity
IEA
GO_REF:0000002 		ACCEPT
Summary: HSPB8 forms stable homodimers, the basic oligomeric unit of this small HSP. Supported by direct biochemical evidence.
Reason: Recombinant HSPB8 forms stable dimers by size-exclusion and crosslinking, corroborating this electronic annotation.
Supporting Evidence:
PMID:14985082
Hsp22 forms stable dimers
GO:0005515 protein binding
IPI
PMID:14594798
Interaction of human HSP22 (HSPB8) with other small heat sho... 		MODIFY
Summary: HSPB8 (HSP22) interacts with the small heat shock proteins HSPB7 (cvHSP), HSPB2 (MKBP) and HSPB1 (HSP27). The bare protein binding term is uninformative; the partners are heat shock proteins.
Reason: Per curation guidelines, bare protein binding (GO:0005515) is uninformative. The documented partners are small HSPs, so heat shock protein binding (GO:0031072) is the appropriate specific molecular function.
Proposed replacements: heat shock protein binding
Supporting Evidence:
PMID:14594798
HSP22 interacts with itself, cvHSP (HSPB7), MKBP (HSPB2) and HSP27
GO:0005515 protein binding
IPI
PMID:16189514
Towards a proteome-scale map of the human protein-protein in... 		KEEP AS NON CORE
Summary: Proteome-scale interactome screen capturing HSPB8 interactions. The bare protein binding term is uninformative.
Reason: High-throughput interactome data records genuine interactions but the bare term is uninformative; HSPB8's biologically meaningful chaperone interactions are captured by more specific terms.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16189514
GO:0005515 protein binding
IPI
PMID:21516116
Next-generation sequencing to generate interactome datasets. 		KEEP AS NON CORE
Summary: Next-generation-sequencing interactome dataset capturing HSPB8 interactions. The bare protein binding term is uninformative.
Reason: High-throughput interactome data; records genuine interactions but uninformative as a molecular function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:21516116
GO:0005515 protein binding
IPI
PMID:23414517
A human skeletal muscle interactome centered on proteins inv... 		KEEP AS NON CORE
Summary: Human skeletal-muscle interactome study capturing HSPB8 interactions in a muscle context. The bare protein binding term is uninformative.
Reason: Muscle-focused interactome data is contextually relevant but the bare term is uninformative as a molecular function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:23414517
GO:0005515 protein binding
IPI
PMID:25036637
A quantitative chaperone interaction network reveals the arc... 		KEEP AS NON CORE
Summary: Quantitative chaperone interaction network capturing HSPB8 within chaperone modules. The bare protein binding term is uninformative.
Reason: Places HSPB8 in the chaperone interactome; genuine but uninformative as a bare molecular-function term.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25036637
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		KEEP AS NON CORE
Summary: Proteome-scale yeast two-hybrid interactome map capturing HSPB8 interactions. The bare protein binding term is uninformative.
Reason: High-throughput interactome data; uninformative as a molecular function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956
GO:0005515 protein binding
IPI
PMID:26496610
A human interactome in three quantitative dimensions organiz... 		KEEP AS NON CORE
Summary: Quantitative stoichiometry-resolved interactome capturing HSPB8 interactions. The bare protein binding term is uninformative.
Reason: High-throughput interactome data; uninformative as a molecular function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:26496610
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		KEEP AS NON CORE
Summary: Human interactome (protein communities) study capturing HSPB8 interactions. The bare protein binding term is uninformative.
Reason: High-throughput interactome data; uninformative as a molecular function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442
GO:0005515 protein binding
IPI
PMID:31273097
The heme-regulated inhibitor is a cytosolic sensor of protei... 		KEEP AS NON CORE
Summary: Study of the heme-regulated inhibitor (HRI) misfolding sensor capturing an HSPB8 interaction. The bare protein binding term is uninformative.
Reason: Records a genuine interaction relevant to a misfolding-stress pathway but the bare term is uninformative as a molecular function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:31273097
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: Reference binary interactome map capturing HSPB8 interactions. The bare protein binding term is uninformative.
Reason: High-throughput interactome data; uninformative as a molecular function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183
GO:0005515 protein binding
IPI
PMID:32707033
Kinase Interaction Network Expands Functional and Disease Ro... 		KEEP AS NON CORE
Summary: Kinase interaction network study capturing HSPB8 interactions. The bare protein binding term is uninformative.
Reason: High-throughput interactome data; uninformative as a molecular function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32707033
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: BioPlex affinity-purification interactome capturing HSPB8 interactions. The bare protein binding term is uninformative.
Reason: High-throughput interactome data; uninformative as a molecular function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781
GO:0042802 identical protein binding
IPI
PMID:14594798
Interaction of human HSP22 (HSPB8) with other small heat sho... 		ACCEPT
Summary: HSPB8 self-associates (HSP22 interacts with itself), the basis for its homodimer/homo-oligomer. Identical protein binding is supported.
Reason: Direct evidence that HSP22 interacts with itself supports the self-association molecular function.
Supporting Evidence:
PMID:14594798
HSP22 interacts with itself, cvHSP (HSPB7), MKBP (HSPB2) and HSP27
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		KEEP AS NON CORE
Summary: Direct immunofluorescence (HPA) localization to the nucleoplasm, consistent with HSPB8's documented nuclear pool.
Reason: Supported by HPA IDA evidence; consistent with nuclear localization but peripheral to the core cytoplasmic CASA/holdase function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005654 nucleoplasm cellular_component ECO:0000314 IDA
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: Direct immunofluorescence (HPA) localization to the cytosol, the principal compartment for HSPB8's chaperone activity.
Reason: IDA-supported cytosolic localization, consistent with the cytoplasmic site of CASA and holdase activity.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005829 cytosol cellular_component ECO:0000314 IDA
GO:0042803 protein homodimerization activity
IPI
PMID:18006506
HspB8 chaperone activity toward poly(Q)-containing proteins ... 		ACCEPT
Summary: HSPB8 homodimerization activity, the basic oligomeric unit of this small HSP, supported by direct evidence.
Reason: HSPB8 forms stable dimers/self-associates; this IPI-supported homodimerization is a genuine molecular function.
Supporting Evidence:
PMID:14985082
Hsp22 forms stable dimers
GO:0005515 protein binding
IPI
PMID:18006506
HspB8 chaperone activity toward poly(Q)-containing proteins ... 		MODIFY
Summary: Demonstrates that HSPB8 forms a stable, functionally essential complex with the co-chaperone BAG3. The bare protein binding term is uninformative; BAG3 is a chaperone/co-chaperone.
Reason: Bare protein binding is uninformative. The documented partner BAG3 is a Hsp70 co-chaperone/scaffold, so protein-folding chaperone binding (GO:0051087) is the appropriate specific molecular function.
Supporting Evidence:
PMID:18006506
HspB8 forms a stable complex with Bag3 in cells and that the formation of this complex is essential for the activity of HspB8
GO:0034620 cellular response to unfolded protein
IMP
PMID:18006506
HspB8 chaperone activity toward poly(Q)-containing proteins ... 		ACCEPT
Summary: HSPB8 overexpression prevents accumulation of aggregation-prone clients (poly-Q Htt43Q); this anti-aggregation activity, dependent on BAG3-stimulated autophagy, is part of the cellular response to unfolded/misfolded protein.
Reason: Direct experimental (IMP) evidence that HSPB8 handles aggregation-prone misfolded clients supports this process annotation as a core function.
Supporting Evidence:
PMID:18006506
overexpression of HspB8 in cultured cells prevents the accumulation of aggregation-prone proteins such as the polyglutamine protein Htt43Q
GO:0101031 protein folding chaperone complex
IDA
PMID:18006506
HspB8 chaperone activity toward poly(Q)-containing proteins ... 		ACCEPT
Summary: HSPB8 forms a stable complex with BAG3 (and within the larger CASA/Hsp70 machinery); direct evidence places it in a chaperone complex.
Reason: Direct (IDA) evidence for a stable HSPB8-BAG3 complex supports membership in a protein-folding chaperone complex.
Supporting Evidence:
PMID:18006506
HspB8 forms a stable complex with Bag3 in cells
GO:1905337 positive regulation of aggrephagy
IMP
PMID:18006506
HspB8 chaperone activity toward poly(Q)-containing proteins ... 		ACCEPT
Summary: HSPB8, in complex with BAG3, promotes the macroautophagic degradation of aggregation-prone clients (Htt43Q). This is the core CASA/aggrephagy role of HSPB8.
Reason: Direct experimental evidence that the HSPB8-BAG3 complex stimulates macroautophagic degradation of poly-Q clients strongly supports positive regulation of aggrephagy as a core biological process.
Supporting Evidence:
PMID:18006506
the HspB8-Bag3 complex might stimulate the degradation of Htt43Q by macroautophagy
GO:0005515 protein binding
IPI
PMID:28144995
Axonal Neuropathies due to Mutations in Small Heat Shock Pro... 		MODIFY
Summary: Disease-variant study documenting the HSPB8-BAG3 interaction (with several HMND2 mutations altering it). The bare protein binding term is uninformative; the partner BAG3 is a co-chaperone.
Reason: Bare protein binding is uninformative. The documented partner is the co-chaperone BAG3, so protein-folding chaperone binding (GO:0051087) is the appropriate specific molecular function.
Supporting Evidence:
file:human/HSPB8/HSPB8-uniprot.txt
Interacts with BAG3 (PubMed:28144995)
GO:0005737 cytoplasm
IDA
PMID:28144995
Axonal Neuropathies due to Mutations in Small Heat Shock Pro... 		ACCEPT
Summary: Direct experimental evidence for cytoplasmic localization of HSPB8 from the disease-variant characterization study.
Reason: IDA-supported cytoplasmic localization, the principal compartment for HSPB8's CASA/holdase function.
Supporting Evidence:
file:human/HSPB8/HSPB8-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19464326, ECO:0000269|PubMed:28144995}
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-5082356 		KEEP AS NON CORE
Summary: Reactome-curated nucleoplasm localization, consistent with the HPA IDA nucleoplasm annotation and HSPB8's nuclear pool.
Reason: Supported by curated pathway annotation and HPA evidence; consistent with nuclear localization but peripheral to the core cytoplasmic function.
Supporting Evidence:
file:human/HSPB8/HSPB8-goa.tsv
GO:0005654 nucleoplasm cellular_component ECO:0000304 TAS Reactome:R-HSA-5082356
GO:0005515 protein binding
IPI
PMID:22366786
Mutations affecting the cytoplasmic functions of the co-chap... 		MODIFY
Summary: Documents the HSPB8 interaction with the co-chaperone DNAJB6 (a Hsp40/J-domain protein mutated in limb-girdle muscular dystrophy). The bare protein binding term is uninformative; the partner is a chaperone.
Reason: Bare protein binding is uninformative. The documented partner DNAJB6 is a J-domain co-chaperone, so heat shock protein binding (GO:0031072) is the appropriate specific molecular function.
Proposed replacements: heat shock protein binding
Supporting Evidence:
file:human/HSPB8/HSPB8-uniprot.txt
Interacts with DNAJB6 (PubMed:22366786)
GO:0004672 protein kinase activity
IDA NOT
PMID:14985082
Some properties of human small heat shock protein Hsp22 (H11... 		ACCEPT
Summary: Although HSPB8 was originally named protein kinase H11, recombinant HSPB8 has negligible autophosphorylation and cannot phosphorylate model substrates; the kinase activity is refuted. The NOT (negated) annotation is correct.
Reason: Direct experimental evidence refutes protein kinase activity for HSPB8, supporting this correctly-negated annotation.
Supporting Evidence:
PMID:14985082
Hsp22 possesses a negligibly low autophosphorylation activity and under the conditions used is unable to phosphorylate casein or
GO:0005634 nucleus
IDA
PMID:19464326
HSPB7 is a SC35 speckle resident small heat shock protein. 		ACCEPT
Summary: Direct experimental (confocal microscopy) evidence for nuclear localization of HSPB8 from the HSPB-family subcellular-distribution survey.
Reason: IDA-supported nuclear localization, consistent with UniProt and the heat-shock-induced nuclear foci.
Supporting Evidence:
file:human/HSPB8/HSPB8-uniprot.txt
Nucleus {ECO:0000269|PubMed:19464326}
GO:0005737 cytoplasm
IDA
PMID:19464326
HSPB7 is a SC35 speckle resident small heat shock protein. 		ACCEPT
Summary: Direct experimental (confocal microscopy) evidence for cytoplasmic localization of HSPB8.
Reason: IDA-supported cytoplasmic localization, the principal site of HSPB8 action.
Supporting Evidence:
file:human/HSPB8/HSPB8-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm

Core Functions

ATP-independent small heat shock protein (holdase) that binds aggregation-prone and stress-destabilized client proteins, preventing their aggregation.

Molecular Function:
unfolded protein binding
Cellular Locations:
cytoplasm
Supporting Evidence:
  • PMID:14985082
    Hsp22 effectively prevents heat-induced aggregation of yeast alcohol dehydrogenase and bovine liver rhodanese
  • PMID:18006506
    overexpression of HspB8 in cultured cells prevents the accumulation of aggregation-prone proteins such as the polyglutamine protein Htt43Q

Co-chaperone partner of BAG3 that, with HSPA8/Hsp70 and STUB1/CHIP, drives chaperone-assisted selective autophagy (CASA), promoting aggrephagy/macroautophagic clearance of damaged clients (e.g. filamin, polyglutamine proteins) for muscle proteostasis.

Molecular Function:
protein-folding chaperone binding
Cellular Locations:
cytoplasm
Supporting Evidence:
  • PMID:18006506
    HspB8 forms a stable complex with Bag3 in cells and that the formation of this complex is essential for the activity of HspB8
  • file:human/HSPB8/HSPB8-uniprot.txt
    Component of the chaperone-assisted selective autophagy (CASA) complex consisting of BAG3, HSPA8/HSC70, HSPB8 and STUB1/CHIP

Positive regulator of aggrephagy / selective autophagy, routing aggregation-prone misfolded clients for autophagic degradation as part of the cellular response to proteotoxic stress.

Molecular Function:
unfolded protein binding
Directly Involved In:
positive regulation of aggrephagy
Cellular Locations:
cytoplasm
Supporting Evidence:
  • PMID:18006506
    the HspB8-Bag3 complex might stimulate the degradation of Htt43Q by macroautophagy

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation of UniProtKB entries based on the manual curation of subcellular locations
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
PMID:14594798
Interaction of human HSP22 (HSPB8) with other small heat shock proteins.
  • HSP22 (HSPB8) self-associates and hetero-dimerizes with HSPB7 (cvHSP), HSPB2 (MKBP) and HSPB1 (HSP27), defining the small-HSP hetero-oligomer network.
PMID:14985082
Some properties of human small heat shock protein Hsp22 (H11 or HspB8).
  • Recombinant HSPB8 forms stable dimers, has negligible kinase/autophosphorylation activity and cannot phosphorylate casein or histone, but possesses ATP-independent chaperone (holdase) activity preventing heat-induced aggregation of alcohol dehydrogenase and rhodanese.
PMID:16189514
Towards a proteome-scale map of the human protein-protein interaction network.
PMID:18006506
HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy.
  • HSPB8 forms a stable complex with BAG3 that is essential for its activity; the HSPB8-BAG3 complex promotes macroautophagic degradation of the polyglutamine protein Htt43Q, preventing accumulation of aggregation-prone proteins.
PMID:19464326
HSPB7 is a SC35 speckle resident small heat shock protein.
  • Confocal-microscopy survey of HSPB-family subcellular distribution; HSPB8 localizes to cytoplasm and nucleus.
PMID:20060297
Chaperone-assisted selective autophagy is essential for muscle maintenance.
  • BAG3 coordinates Hsc70 (HSPA8) and the small HSP HSPB8 in chaperone-assisted selective autophagy (CASA), initiated by the ubiquitin ligase CHIP/STUB1 and the autophagy adaptor p62, to degrade damaged Z-disk components such as filamin; impaired CASA causes Z-disk disintegration and progressive muscle weakness.
PMID:21516116
Next-generation sequencing to generate interactome datasets.
PMID:22366786
Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.
  • HSPB8 interacts with the J-domain co-chaperone DNAJB6, linking it to the chaperone network whose disruption causes limb-girdle muscular dystrophy.
PMID:23414517
A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome.
PMID:25036637
A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:26496610
A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
PMID:28144995
Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations.
  • Characterized HMND2-causing HSPB8 variants; documents HSPB8-BAG3 interaction and that several mutations alter it, with cytoplasmic localization of HSPB8.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:31273097
The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:32707033
Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
Reactome:R-HSA-5082356
Reactome annotation (nucleoplasm localization of HSPB8)
file:human/HSPB8/HSPB8-uniprot.txt
UniProt entry Q9UJY1 (HSPB8_HUMAN), Heat shock protein beta-8 (HSP22)
  • Small heat shock protein involved in chaperone-assisted selective autophagy (CASA) with BAG3, HSPA8/HSC70 and STUB1/CHIP; temperature-dependent chaperone activity; interacts with HSPB1, DNAJB6, BAG3 and HSPA1A; cytoplasm and nucleus; muscle-enriched; dominant variants cause HMND2/CMT2L/MFM13.

Suggested Questions for Experts

Q: How do the K141 hot-spot variants mechanistically impair HSPB8 chaperone function and CASA to cause the spectrum of neuropathy and myopathy phenotypes?

Q: What determines the client selectivity of HSPB8 within the BAG3/Hsp70 CASA machinery versus its standalone holdase activity?

Q: Does the nuclear pool of HSPB8 have a function distinct from its cytoplasmic CASA role?

Suggested Experiments

Experiment: Reconstitute the CASA complex (HSPB8/BAG3/HSPA8/STUB1) in vitro and measure HSPB8-dependent ubiquitination and autophagic targeting of a model damaged client (e.g. filamin), comparing wild-type and K141 variants.

Experiment: Quantitative autophagy-flux and aggregate-clearance assays in HSPB8-null versus reconstituted muscle cells with poly-Q or aggregation-prone reporters.

Experiment: Knock-in mouse or iPSC-derived motor neuron/myocyte models of HSPB8 K141N/E to assess Z-disk integrity, aggrephagy, and progressive degeneration.

📚 Additional Documentation

Notes

(HSPB8-notes.md)

HSPB8 (Q9UJY1) research notes

Identity

  • Heat shock protein beta-8 / HSP22 / H11 / E2IG1 / alpha-crystallin C chain, small heat shock protein (HSP20/alpha-crystallin) family, 196 aa, ~21.6 kDa.
  • Predominantly expressed in skeletal muscle and heart [file:human/HSPB8/HSPB8-uniprot.txt "Predominantly expressed in skeletal muscle and heart."]. Estrogen-inducible (E2IG1).

Function (core)

  • UniProt FUNCTION: "Involved in the chaperone-assisted selective autophagy (CASA), a crucial process for protein quality control, particularly in mechanical strained cells and tissues such as muscle. Displays temperature-dependent chaperone activity." [file:human/HSPB8/HSPB8-uniprot.txt].
  • ATP-independent holdase activity demonstrated in vitro: prevents heat-induced aggregation of yeast alcohol dehydrogenase and bovine rhodanese, comparable to HSP20 PMID:14985082.
  • NOT a protein kinase: despite early naming as "protein kinase H11", recombinant Hsp22 has "negligibly low autophosphorylation activity and...is unable to phosphorylate casein or histone" PMID:14985082. The NOT|protein kinase activity annotation (GO:0004672, IDA, PMID:14985082) is supported.

CASA / aggrephagy mechanism

  • Component of the CASA complex: BAG3, HSPA8/HSC70, HSPB8, STUB1/CHIP [file:human/HSPB8/HSPB8-uniprot.txt "Component of the chaperone-assisted selective autophagy (CASA) complex consisting of BAG3, HSPA8/HSC70, HSPB8 and STUB1/CHIP (PubMed:20060297)."].
  • CASA facilitates degradation of damaged Z-disk components (e.g. filamin) via autophagy; BAG3 coordinates Hsc70 and HspB8; CHIP ubiquitin ligase and p62 adaptor [PMID:20060297 "Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the small heat shock protein HspB8 during disposal that is initiated by the chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin adaptor p62."; "Impaired CASA results in Z disk disintegration and progressive muscle weakness in flies, mice, and men."].
  • HspB8 chaperone activity toward poly(Q) proteins depends on Bag3-stimulated macroautophagy [PMID:18006506 "HspB8 forms a stable complex with Bag3 in cells and that the formation of this complex is essential for the activity of HspB8."; "the HspB8-Bag3 complex might stimulate the degradation of Htt43Q by macroautophagy."]. This is the basis for the positive regulation of aggrephagy (GO:1905337, IMP) and cellular response to unfolded protein (GO:0034620, IMP) annotations.
  • Forms ternary complex with BAG3 and HSPA1A (Hsp70) [PMID:27884606 BAG3 links Hsp70 to small HSPs]. Interacts with HSPB1 PMID:11342557, DNAJB6 PMID:22366786, HSPB7/HSPB2 PMID:14594798.

Oligomerization

  • Forms stable dimers / homodimerization PMID:14985082. GO:0042803 (protein homodimerization activity) and GO:0042802 (identical protein binding) supported.

Localization

  • Cytoplasm and nucleus; translocates to nuclear foci during heat shock [file:human/HSPB8/HSPB8-uniprot.txt "Cytoplasm ... Nucleus ... Note=Translocates to nuclear foci during heat shock."]. GOA: cytosol (IDA, HPA), nucleoplasm (IDA, HPA), protein folding chaperone complex (IDA).

Disease

  • Distal hereditary motor neuronopathy type 2 (HMND2), Charcot-Marie-Tooth type 2L (CMT2L), myofibrillar myopathy 13 (MFM13). Hot-spot K141 variants (K141E/N/M/T) affect chaperone function, increase aggregation, and alter BAG3/HSPB1 interactions [file:human/HSPB8/HSPB8-uniprot.txt VARIANT 141; PMID:15122253; PMID:28144995].

GO review plan

  • Core MF: unfolded protein binding / holdase (GO:0051082) and Hsp70-co-chaperone CASA role. Core BP: positive regulation of aggrephagy (GO:1905337) and CASA.
  • Many bare protein binding IPIs (GO:0005515): the BAG3 (O95817), HSPB1, DNAJB6, HSPB7 ones are informative -> heat shock protein binding / chaperone binding; the generic interactome ones KEEP_AS_NON_CORE.
  • protein folding chaperone complex (GO:0101031, part_of): ACCEPT (CASA complex / sHSP complex).
  • NOT protein kinase activity (GO:0004672 negated): ACCEPT - correctly negated.

Pn Notes

(HSPB8-pn-notes.md)

HSPB8 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9UJY1
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07b
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: HSPB8 (heat shock protein beta-8, also called HSP22, H11 kinase, E2IG1 or alpha-crystallin C chain) is a member of the small heat shock protein (sHSP / HSP20, alpha-crystallin domain) family, predominantly expressed in skeletal muscle and heart. It is an ATP-independent molecular chaperone (holdase) that binds aggregation-prone and stress-destabilized client proteins. Its central role is in chaperone-assisted selective autophagy (CASA), where together with the co-chaperone BAG3, the Hsp70 chaperones HSPA8/HSC70 and HSPA1A, and the ubiquitin ligase STUB1/CHIP, HSPB8 routes damaged clients (e.g. filamin and polyglutamine-expanded proteins) for autophagic degradation via p62/SQSTM1, a process essential for maintenance of the muscle Z-disk under mechanical stress. HSPB8 forms homodimers and hetero-oligomers with other small HSPs (HSPB1, HSPB2, HSPB7) and DNAJB6. Despite an early report of protein kinase activity, recombinant HSPB8 lacks detectable kinase activity. It localizes to the cytoplasm and nucleus and translocates to nuclear foci during heat shock. Dominant variants (notably at the K141 hot spot) cause distal hereditary motor neuropathy, Charcot-Marie-Tooth disease type 2L, and myofibrillar/rimmed-vacuole myopathy.
  • Existing/core annotation action counts: ACCEPT: 18; KEEP_AS_NON_CORE: 13; MODIFY: 4

PN Consistency Summary

  • Consistency: Best-evidenced of the six and fully consistent across notes ↔ review ↔ PN CASA row. HSPB8/HSP22 is an ATP-independent holdase (PMID:14985082) and the sHSP of the CASA complex with BAG3/HSPA8/STUB1 driving aggrephagy of polyQ/filamin (PMID:18006506, 20060297). The PN CASA row even cites matching CASA papers. Mitochondrial row is unsupported (HSPB8 documented in cytoplasm/nucleus, not mitochondria).
  • PN story / NEW pressure: The CASA/aggrephagy story is ALREADY captured: review has GO:1905337 positive regulation of aggrephagy (IMP) and GO:0034620 cellular response to unfolded protein; GOA carries GO:1905337. PN's GO:0035973 aggrephagy is the parent process and is correctly flagged supported_by_goa_regulation — already captured. The sHSP GO:0044183 projection is the same foldase-vs-holdase over-reach as the other sHSPs (HSPB8 is a holdase per PMID:14985082; GOA has no folding-chaperone MF, core MF is GO:0051082 unfolded protein binding + GO:0051087 protein-folding chaperone binding for the BAG3 interaction).
  • Evidence alignment: Strong overlap — PN CASA-row titles (CASA complex dynamics; HspB8 promotes autophagic removal in ALS; HSPB8-BAG3-HSP70 stress-granule surveillance) align with the review's CASA PMIDs (18006506, 20060297). No divergence on the autophagy story.
  • Verdict: CASA/aggrephagy projection sound and already captured; sHSP foldase MF over-reaches, mito row unsupported. Recommended edits: [MAP] retarget sHSP GO:0044183 → GO:0140309 / GO:0051082 on Q9UJY1; [MAP] do not project a mitochondrial chaperone term onto HSPB8 (no mito localization). CASA row needs no change.

Full Consistency Review

  • UniProt: Q9UJY1 · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: three rows — Cytonuclear proteostasis|...|small HSP (type), Mitochondrial proteostasis|Chaperone|small HSP (group), and Autophagy-Lysosome Pathway|...|Chaperone assisted selective autophagy|CASA complex component (subtype) ; PN-node mapping: sHSP nodes → mapped/ok GO:0044183 protein folding chaperone (new_to_goa); CASA subtype → mapped/ok GO:0035973 aggrephagy (supported_by_goa_regulation).
  • Consistency: Best-evidenced of the six and fully consistent across notes ↔ review ↔ PN CASA row. HSPB8/HSP22 is an ATP-independent holdase (PMID:14985082) and the sHSP of the CASA complex with BAG3/HSPA8/STUB1 driving aggrephagy of polyQ/filamin (PMID:18006506, 20060297). The PN CASA row even cites matching CASA papers. Mitochondrial row is unsupported (HSPB8 documented in cytoplasm/nucleus, not mitochondria).
  • PN story / NEW pressure: The CASA/aggrephagy story is ALREADY captured: review has GO:1905337 positive regulation of aggrephagy (IMP) and GO:0034620 cellular response to unfolded protein; GOA carries GO:1905337. PN's GO:0035973 aggrephagy is the parent process and is correctly flagged supported_by_goa_regulation — already captured. The sHSP GO:0044183 projection is the same foldase-vs-holdase over-reach as the other sHSPs (HSPB8 is a holdase per PMID:14985082; GOA has no folding-chaperone MF, core MF is GO:0051082 unfolded protein binding + GO:0051087 protein-folding chaperone binding for the BAG3 interaction).
  • Mapping strategy: CASA subtype → GO:0035973 needs no change (already covered by stronger GO:1905337 in review/GOA). The sHSP GO:0044183 target is the wrong MF (foldase) for this holdase; prefer GO:0140309 holdase / GO:0051082. Drop the mitochondrial-row chaperone projection.
  • Evidence alignment: Strong overlap — PN CASA-row titles (CASA complex dynamics; HspB8 promotes autophagic removal in ALS; HSPB8-BAG3-HSP70 stress-granule surveillance) align with the review's CASA PMIDs (18006506, 20060297). No divergence on the autophagy story.
  • Verdict: CASA/aggrephagy projection sound and already captured; sHSP foldase MF over-reaches, mito row unsupported. Recommended edits: [MAP] retarget sHSP GO:0044183 → GO:0140309 / GO:0051082 on Q9UJY1; [MAP] do not project a mitochondrial chaperone term onto HSPB8 (no mito localization). CASA row needs no change.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/HSPB8/HSPB8-ai-review.yaml
  • PN workbook rows: 3

PN row 1: Cytonuclear proteostasis | Chaperone | small HSP system | small HSP

  • UniProt: Q9UJY1
  • In branches: CY, MI, ALP
  • PN-node mapping records (path + ancestors):
    • [type] Cytonuclear proteostasis|Chaperone|small HSP system|small HSP
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0044183 protein folding chaperone]
      rationale: This PN type denotes small heat-shock chaperones. Protein folding chaperone is the appropriate shared molecular-function term.
    • [group] Cytonuclear proteostasis|Chaperone|small HSP system
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower taxonomy bucket that is already covered by a curated parent mapping or by gene-level annotations. No additional direct GO mapping is appropriate from this node.
    • [class] Cytonuclear proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [branch] Cytonuclear proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: Mitochondrial proteostasis | Chaperone | small HSP

  • UniProt: Q9UJY1
  • In branches: CY, MI, ALP
  • PN-node mapping records (path + ancestors):
    • [group] Mitochondrial proteostasis|Chaperone|small HSP
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0044183 protein folding chaperone]
      rationale: This PN group denotes mitochondrial small heat-shock chaperones. Protein folding chaperone is the appropriate shared molecular-function term.
    • [class] Mitochondrial proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: This PN class is too heterogeneous for a single safe GO mapping. In the workbook it mixes HSP70, HSP60, and HSP90 systems, small intermembrane-space chaperones, membrane-protein chaperones, and other mitochondrial-specific factors.
    • [branch] Mitochondrial proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 3: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | Chaperone assisted selective autophagy | CASA complex component

  • UniProt: Q9UJY1
  • In branches: CY, MI, ALP
  • Notes: Small heat shock protein. Participates in chaperone-assisted selective autophagy by forming the CASA complex (HSPA8, BAG3, HSPB8, and STUB1) that delivers ubiquitinated substrates to the to the autophagosome
  • PN references (titles):
    • Full article: The chaperone-assisted selective autophagy complex dynamics and dysfunctions (tandfonline.com)
    • small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS) | Human Molecular Genetics | Oxford Academic (oup.com)
    • A Surveillance Function of the HSPB8-BAG3-HSP70 Chaperone Complex Ensures Stress Granule Integrity and Dynamism - ScienceDirect
  • PN-node mapping records (path + ancestors):
    • [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Chaperone assisted selective autophagy|CASA complex component
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0035973 aggrephagy]
      rationale: The PN CASA subtype covers BAG3-HSPB8-HSP70-system machinery that directs damaged or aggregation-prone substrates into selective autophagic clearance. GO lacks a dedicated CASA term in the current cache, and this subtype includes chaperones and cofactors beyond pure cargo adaptors, so aggrephagy is the closest available process target.
    • [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Chaperone assisted selective autophagy
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
    • [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

  • GO:0044183 protein folding chaperone | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Cytonuclear proteostasis|Chaperone|small HSP system|small HSP
  • GO:0044183 protein folding chaperone | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Mitochondrial proteostasis|Chaperone|small HSP
  • GO:0035973 aggrephagy | scope=ok_for_propagation_to_go | goa_status=supported_by_goa_regulation | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Chaperone assisted selective autophagy|CASA complex component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: Q9UJY1
gene_symbol: HSPB8
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: HSPB8 (heat shock protein beta-8, also called HSP22, H11 kinase, E2IG1 or alpha-crystallin C chain) is a member of the small heat shock protein (sHSP / HSP20, alpha-crystallin domain) family, predominantly expressed in skeletal muscle and heart. It is an ATP-independent molecular chaperone (holdase) that binds aggregation-prone and stress-destabilized client proteins. Its central role is in chaperone-assisted selective autophagy (CASA), where together with the co-chaperone BAG3, the Hsp70 chaperones HSPA8/HSC70 and HSPA1A, and the ubiquitin ligase STUB1/CHIP, HSPB8 routes damaged clients (e.g. filamin and polyglutamine-expanded proteins) for autophagic degradation via p62/SQSTM1, a process essential for maintenance of the muscle Z-disk under mechanical stress. HSPB8 forms homodimers and hetero-oligomers with other small HSPs (HSPB1, HSPB2, HSPB7) and DNAJB6. Despite an early report of protein kinase activity, recombinant HSPB8 lacks detectable kinase activity. It localizes to the cytoplasm and nucleus and translocates to nuclear foci during heat shock. Dominant variants (notably at the K141 hot spot) cause distal hereditary motor neuropathy, Charcot-Marie-Tooth disease type 2L, and myofibrillar/rimmed-vacuole myopathy.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Nuclear localization inferred phylogenetically; HSPB8 is directly documented in the nucleus and translocates to nuclear foci during heat shock.
    action: ACCEPT
    reason: Corroborated by direct experimental (IDA) evidence (PMID:19464326) and the UniProt subcellular-location record.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:19464326}
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Cytoplasmic localization inferred phylogenetically; the cytoplasm is the principal site where HSPB8 acts in CASA and as a holdase.
    action: ACCEPT
    reason: Corroborated by direct experimental (IDA) evidence (PMID:19464326, PMID:28144995) and the UniProt subcellular-location record.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0034620
    label: cellular response to unfolded protein
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: As a stress-inducible small HSP holdase, HSPB8 participates in the cellular response to unfolded protein. Supported by family inference and by direct functional data.
    action: ACCEPT
    reason: Phylogenetic inference is consistent with experimental evidence that HSPB8 prevents aggregation of unfolded/aggregation-prone clients and is induced by stress.
    supported_by:
    - reference_id: PMID:14985082
      supporting_text: Hsp22 effectively prevents heat-induced aggregation of yeast alcohol dehydrogenase and bovine liver rhodanese
- term:
    id: GO:0101031
    label: protein folding chaperone complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: HSPB8 is a component of multi-chaperone complexes (the CASA complex with BAG3/HSPA8/STUB1, and sHSP hetero-oligomers). Membership in a protein-folding chaperone complex is well supported.
    action: ACCEPT
    reason: Direct experimental evidence places HSPB8 in the CASA complex and in ternary complexes with BAG3 and Hsp70, consistent with this phylogenetic annotation.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
      supporting_text: Component of the chaperone-assisted selective autophagy (CASA) complex consisting of BAG3, HSPA8/HSC70, HSPB8 and STUB1/CHIP
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of nuclear localization, consistent with the IBA and IDA nucleus annotations.
    action: ACCEPT
    reason: Agrees with stronger experimental evidence (PMID:19464326) placing HSPB8 in the nucleus.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:19464326}
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of cytoplasmic localization, redundant with the IBA and IDA cytoplasm annotations.
    action: ACCEPT
    reason: Correct compartment, agreeing with stronger experimental evidence.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0034620
    label: cellular response to unfolded protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic annotation to the cellular response to unfolded protein, consistent with HSPB8's sHSP holdase function.
    action: ACCEPT
    reason: Redundant with the IBA and IMP annotations of the same process, all supported by HSPB8's documented anti-aggregation chaperone activity.
    supported_by:
    - reference_id: PMID:14985082
      supporting_text: Hsp22 effectively prevents heat-induced aggregation of yeast alcohol dehydrogenase and bovine liver rhodanese
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: HSPB8 forms stable homodimers, the basic oligomeric unit of this small HSP. Supported by direct biochemical evidence.
    action: ACCEPT
    reason: Recombinant HSPB8 forms stable dimers by size-exclusion and crosslinking, corroborating this electronic annotation.
    supported_by:
    - reference_id: PMID:14985082
      supporting_text: Hsp22 forms stable dimers
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14594798
  qualifier: enables
  review:
    summary: HSPB8 (HSP22) interacts with the small heat shock proteins HSPB7 (cvHSP), HSPB2 (MKBP) and HSPB1 (HSP27). The bare protein binding term is uninformative; the partners are heat shock proteins.
    action: MODIFY
    reason: Per curation guidelines, bare protein binding (GO:0005515) is uninformative. The documented partners are small HSPs, so heat shock protein binding (GO:0031072) is the appropriate specific molecular function.
    proposed_replacement_terms:
    - id: GO:0031072
      label: heat shock protein binding
    supported_by:
    - reference_id: PMID:14594798
      supporting_text: HSP22 interacts with itself, cvHSP (HSPB7), MKBP (HSPB2) and HSP27
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Proteome-scale interactome screen capturing HSPB8 interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data records genuine interactions but the bare term is uninformative; HSPB8's biologically meaningful chaperone interactions are captured by more specific terms.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16189514
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: Next-generation-sequencing interactome dataset capturing HSPB8 interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data; records genuine interactions but uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:21516116
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23414517
  qualifier: enables
  review:
    summary: Human skeletal-muscle interactome study capturing HSPB8 interactions in a muscle context. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Muscle-focused interactome data is contextually relevant but the bare term is uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:23414517
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: Quantitative chaperone interaction network capturing HSPB8 within chaperone modules. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Places HSPB8 in the chaperone interactome; genuine but uninformative as a bare molecular-function term.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25036637
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale yeast two-hybrid interactome map capturing HSPB8 interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data; uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: Quantitative stoichiometry-resolved interactome capturing HSPB8 interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data; uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:26496610
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Human interactome (protein communities) study capturing HSPB8 interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data; uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31273097
  qualifier: enables
  review:
    summary: Study of the heme-regulated inhibitor (HRI) misfolding sensor capturing an HSPB8 interaction. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a genuine interaction relevant to a misfolding-stress pathway but the bare term is uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:31273097
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Reference binary interactome map capturing HSPB8 interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data; uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  qualifier: enables
  review:
    summary: Kinase interaction network study capturing HSPB8 interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data; uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32707033
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome capturing HSPB8 interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data; uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:14594798
  qualifier: enables
  review:
    summary: HSPB8 self-associates (HSP22 interacts with itself), the basis for its homodimer/homo-oligomer. Identical protein binding is supported.
    action: ACCEPT
    reason: Direct evidence that HSP22 interacts with itself supports the self-association molecular function.
    supported_by:
    - reference_id: PMID:14594798
      supporting_text: HSP22 interacts with itself, cvHSP (HSPB7), MKBP (HSPB2) and HSP27
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) localization to the nucleoplasm, consistent with HSPB8's documented nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Supported by HPA IDA evidence; consistent with nuclear localization but peripheral to the core cytoplasmic CASA/holdase function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005654 nucleoplasm cellular_component ECO:0000314 IDA
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) localization to the cytosol, the principal compartment for HSPB8's chaperone activity.
    action: ACCEPT
    reason: IDA-supported cytosolic localization, consistent with the cytoplasmic site of CASA and holdase activity.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000314 IDA
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:18006506
  qualifier: enables
  review:
    summary: HSPB8 homodimerization activity, the basic oligomeric unit of this small HSP, supported by direct evidence.
    action: ACCEPT
    reason: HSPB8 forms stable dimers/self-associates; this IPI-supported homodimerization is a genuine molecular function.
    supported_by:
    - reference_id: PMID:14985082
      supporting_text: Hsp22 forms stable dimers
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18006506
  qualifier: enables
  review:
    summary: Demonstrates that HSPB8 forms a stable, functionally essential complex with the co-chaperone BAG3. The bare protein binding term is uninformative; BAG3 is a chaperone/co-chaperone.
    action: MODIFY
    reason: Bare protein binding is uninformative. The documented partner BAG3 is a Hsp70 co-chaperone/scaffold, so protein-folding chaperone binding (GO:0051087) is the appropriate specific molecular function.
    proposed_replacement_terms:
    - id: GO:0051087
      label: protein-folding chaperone binding
    supported_by:
    - reference_id: PMID:18006506
      supporting_text: HspB8 forms a stable complex with Bag3 in cells and that the formation of this complex is essential for the activity of HspB8
- term:
    id: GO:0034620
    label: cellular response to unfolded protein
  evidence_type: IMP
  original_reference_id: PMID:18006506
  qualifier: involved_in
  review:
    summary: HSPB8 overexpression prevents accumulation of aggregation-prone clients (poly-Q Htt43Q); this anti-aggregation activity, dependent on BAG3-stimulated autophagy, is part of the cellular response to unfolded/misfolded protein.
    action: ACCEPT
    reason: Direct experimental (IMP) evidence that HSPB8 handles aggregation-prone misfolded clients supports this process annotation as a core function.
    supported_by:
    - reference_id: PMID:18006506
      supporting_text: overexpression of HspB8 in cultured cells prevents the accumulation of aggregation-prone proteins such as the polyglutamine protein Htt43Q
- term:
    id: GO:0101031
    label: protein folding chaperone complex
  evidence_type: IDA
  original_reference_id: PMID:18006506
  qualifier: part_of
  review:
    summary: HSPB8 forms a stable complex with BAG3 (and within the larger CASA/Hsp70 machinery); direct evidence places it in a chaperone complex.
    action: ACCEPT
    reason: Direct (IDA) evidence for a stable HSPB8-BAG3 complex supports membership in a protein-folding chaperone complex.
    supported_by:
    - reference_id: PMID:18006506
      supporting_text: HspB8 forms a stable complex with Bag3 in cells
- term:
    id: GO:1905337
    label: positive regulation of aggrephagy
  evidence_type: IMP
  original_reference_id: PMID:18006506
  qualifier: involved_in
  review:
    summary: HSPB8, in complex with BAG3, promotes the macroautophagic degradation of aggregation-prone clients (Htt43Q). This is the core CASA/aggrephagy role of HSPB8.
    action: ACCEPT
    reason: Direct experimental evidence that the HSPB8-BAG3 complex stimulates macroautophagic degradation of poly-Q clients strongly supports positive regulation of aggrephagy as a core biological process.
    supported_by:
    - reference_id: PMID:18006506
      supporting_text: the HspB8-Bag3 complex might stimulate the degradation of Htt43Q by macroautophagy
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28144995
  qualifier: enables
  review:
    summary: Disease-variant study documenting the HSPB8-BAG3 interaction (with several HMND2 mutations altering it). The bare protein binding term is uninformative; the partner BAG3 is a co-chaperone.
    action: MODIFY
    reason: Bare protein binding is uninformative. The documented partner is the co-chaperone BAG3, so protein-folding chaperone binding (GO:0051087) is the appropriate specific molecular function.
    proposed_replacement_terms:
    - id: GO:0051087
      label: protein-folding chaperone binding
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
      supporting_text: Interacts with BAG3 (PubMed:28144995)
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:28144995
  qualifier: located_in
  review:
    summary: Direct experimental evidence for cytoplasmic localization of HSPB8 from the disease-variant characterization study.
    action: ACCEPT
    reason: IDA-supported cytoplasmic localization, the principal compartment for HSPB8's CASA/holdase function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19464326, ECO:0000269|PubMed:28144995}'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5082356
  qualifier: located_in
  review:
    summary: Reactome-curated nucleoplasm localization, consistent with the HPA IDA nucleoplasm annotation and HSPB8's nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Supported by curated pathway annotation and HPA evidence; consistent with nuclear localization but peripheral to the core cytoplasmic function.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-goa.tsv
      supporting_text: GO:0005654 nucleoplasm cellular_component ECO:0000304 TAS Reactome:R-HSA-5082356
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22366786
  qualifier: enables
  review:
    summary: Documents the HSPB8 interaction with the co-chaperone DNAJB6 (a Hsp40/J-domain protein mutated in limb-girdle muscular dystrophy). The bare protein binding term is uninformative; the partner is a chaperone.
    action: MODIFY
    reason: Bare protein binding is uninformative. The documented partner DNAJB6 is a J-domain co-chaperone, so heat shock protein binding (GO:0031072) is the appropriate specific molecular function.
    proposed_replacement_terms:
    - id: GO:0031072
      label: heat shock protein binding
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
      supporting_text: Interacts with DNAJB6 (PubMed:22366786)
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:14985082
  qualifier: enables
  negated: true
  review:
    summary: Although HSPB8 was originally named protein kinase H11, recombinant HSPB8 has negligible autophosphorylation and cannot phosphorylate model substrates; the kinase activity is refuted. The NOT (negated) annotation is correct.
    action: ACCEPT
    reason: Direct experimental evidence refutes protein kinase activity for HSPB8, supporting this correctly-negated annotation.
    supported_by:
    - reference_id: PMID:14985082
      supporting_text: Hsp22 possesses a negligibly low autophosphorylation activity and under the conditions used is unable to phosphorylate casein or
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:19464326
  qualifier: located_in
  review:
    summary: Direct experimental (confocal microscopy) evidence for nuclear localization of HSPB8 from the HSPB-family subcellular-distribution survey.
    action: ACCEPT
    reason: IDA-supported nuclear localization, consistent with UniProt and the heat-shock-induced nuclear foci.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:19464326}
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:19464326
  qualifier: located_in
  review:
    summary: Direct experimental (confocal microscopy) evidence for cytoplasmic localization of HSPB8.
    action: ACCEPT
    reason: IDA-supported cytoplasmic localization, the principal site of HSPB8 action.
    supported_by:
    - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation of UniProtKB entries based on the manual curation of subcellular locations
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:14594798
  title: Interaction of human HSP22 (HSPB8) with other small heat shock proteins.
  findings:
  - statement: HSP22 (HSPB8) self-associates and hetero-dimerizes with HSPB7 (cvHSP), HSPB2 (MKBP) and HSPB1 (HSP27), defining the small-HSP hetero-oligomer network.
    reference_section_type: RESULTS
- id: PMID:14985082
  title: Some properties of human small heat shock protein Hsp22 (H11 or HspB8).
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_14985082.md title matches; the cached Results establish ATP-independent holdase activity (suppresses heat aggregation of ADH and rhodanese), supporting core_function GO:0051082. Notably the same paper reports negligible kinase activity, which contradicts the GOA IDA GO:0004672 (protein kinase activity) tied to this PMID - a likely over-annotation. Cited in core_functions supported_by."
  findings:
  - statement: Recombinant HSPB8 forms stable dimers, has negligible kinase/autophosphorylation activity and cannot phosphorylate casein or histone, but possesses ATP-independent chaperone (holdase) activity preventing heat-induced aggregation of alcohol dehydrogenase and rhodanese.
    reference_section_type: RESULTS
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:18006506
  title: HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_18006506.md title matches; richly anchored in GOA as the source for GO:1905337 (positive regulation of aggrephagy, IMP), GO:0034620 (cellular response to unfolded protein, IMP), GO:0101031 (protein folding chaperone complex, IDA) and GO:0042803 (homodimerization). Establishes the HSPB8-BAG3 CASA/aggrephagy core function. Cited in core_functions supported_by."
  findings:
  - statement: HSPB8 forms a stable complex with BAG3 that is essential for its activity; the HSPB8-BAG3 complex promotes macroautophagic degradation of the polyglutamine protein Htt43Q, preventing accumulation of aggregation-prone proteins.
    reference_section_type: RESULTS
- id: PMID:19464326
  title: HSPB7 is a SC35 speckle resident small heat shock protein.
  findings:
  - statement: Confocal-microscopy survey of HSPB-family subcellular distribution; HSPB8 localizes to cytoplasm and nucleus.
    reference_section_type: RESULTS
- id: PMID:20060297
  title: Chaperone-assisted selective autophagy is essential for muscle maintenance.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_20060297.md title matches and confirms HSPB8 as a small-HSP component of the BAG3/HSPA8/CHIP chaperone-assisted selective autophagy (CASA) machinery degrading damaged Z-disk filamin in muscle; supports the CASA/aggrephagy core function. Not directly GOA-anchored for HSPB8 but cached content is on-target."
  findings:
  - statement: BAG3 coordinates Hsc70 (HSPA8) and the small HSP HSPB8 in chaperone-assisted selective autophagy (CASA), initiated by the ubiquitin ligase CHIP/STUB1 and the autophagy adaptor p62, to degrade damaged Z-disk components such as filamin; impaired CASA causes Z-disk disintegration and progressive muscle weakness.
    reference_section_type: RESULTS
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
- id: PMID:22366786
  title: Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.
  findings:
  - statement: HSPB8 interacts with the J-domain co-chaperone DNAJB6, linking it to the chaperone network whose disruption causes limb-girdle muscular dystrophy.
    reference_section_type: RESULTS
- id: PMID:23414517
  title: 'A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome.'
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
  findings: []
- id: PMID:28144995
  title: 'Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations.'
  findings:
  - statement: Characterized HMND2-causing HSPB8 variants; documents HSPB8-BAG3 interaction and that several mutations alter it, with cytoplasmic localization of HSPB8.
    reference_section_type: RESULTS
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:31273097
  title: The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32707033
  title: Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: Reactome:R-HSA-5082356
  title: Reactome annotation (nucleoplasm localization of HSPB8)
  findings: []
- id: file:human/HSPB8/HSPB8-uniprot.txt
  title: UniProt entry Q9UJY1 (HSPB8_HUMAN), Heat shock protein beta-8 (HSP22)
  findings:
  - statement: Small heat shock protein involved in chaperone-assisted selective autophagy (CASA) with BAG3, HSPA8/HSC70 and STUB1/CHIP; temperature-dependent chaperone activity; interacts with HSPB1, DNAJB6, BAG3 and HSPA1A; cytoplasm and nucleus; muscle-enriched; dominant variants cause HMND2/CMT2L/MFM13.
    reference_section_type: OTHER
core_functions:
- description: ATP-independent small heat shock protein (holdase) that binds aggregation-prone and stress-destabilized client proteins, preventing their aggregation.
  molecular_function:
    id: GO:0051082
    label: unfolded protein binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:14985082
    supporting_text: Hsp22 effectively prevents heat-induced aggregation of yeast alcohol dehydrogenase and bovine liver rhodanese
  - reference_id: PMID:18006506
    supporting_text: overexpression of HspB8 in cultured cells prevents the accumulation of aggregation-prone proteins such as the polyglutamine protein Htt43Q
- description: Co-chaperone partner of BAG3 that, with HSPA8/Hsp70 and STUB1/CHIP, drives chaperone-assisted selective autophagy (CASA), promoting aggrephagy/macroautophagic clearance of damaged clients (e.g. filamin, polyglutamine proteins) for muscle proteostasis.
  molecular_function:
    id: GO:0051087
    label: protein-folding chaperone binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:18006506
    supporting_text: HspB8 forms a stable complex with Bag3 in cells and that the formation of this complex is essential for the activity of HspB8
  - reference_id: file:human/HSPB8/HSPB8-uniprot.txt
    supporting_text: Component of the chaperone-assisted selective autophagy (CASA) complex consisting of BAG3, HSPA8/HSC70, HSPB8 and STUB1/CHIP
- description: Positive regulator of aggrephagy / selective autophagy, routing aggregation-prone misfolded clients for autophagic degradation as part of the cellular response to proteotoxic stress.
  molecular_function:
    id: GO:0051082
    label: unfolded protein binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:18006506
    supporting_text: the HspB8-Bag3 complex might stimulate the degradation of Htt43Q by macroautophagy
  directly_involved_in:
  - id: GO:1905337
    label: positive regulation of aggrephagy
proposed_new_terms: []
suggested_questions:
- question: How do the K141 hot-spot variants mechanistically impair HSPB8 chaperone function and CASA to cause the spectrum of neuropathy and myopathy phenotypes?
- question: What determines the client selectivity of HSPB8 within the BAG3/Hsp70 CASA machinery versus its standalone holdase activity?
- question: Does the nuclear pool of HSPB8 have a function distinct from its cytoplasmic CASA role?
suggested_experiments:
- description: Reconstitute the CASA complex (HSPB8/BAG3/HSPA8/STUB1) in vitro and measure HSPB8-dependent ubiquitination and autophagic targeting of a model damaged client (e.g. filamin), comparing wild-type and K141 variants.
- description: Quantitative autophagy-flux and aggregate-clearance assays in HSPB8-null versus reconstituted muscle cells with poly-Q or aggregation-prone reporters.
- description: Knock-in mouse or iPSC-derived motor neuron/myocyte models of HSPB8 K141N/E to assess Z-disk integrity, aggrephagy, and progressive degeneration.