id: Q9UBY9 gene_symbol: HSPB7 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: HSPB7 (heat shock protein beta-7), also known as cardiovascular heat shock protein (cvHsp), is a member of the small heat shock protein (sHSP / HSP20, alpha-crystallin domain) family. It is selectively and highly expressed in cardiovascular and insulin-sensitive tissues, predominantly heart and skeletal muscle. HSPB7 binds the actin-crosslinking protein filamin (alpha-filamin / actin-binding protein 280) through its core alpha-crystallin domain and forms hetero-oligomeric complexes with other small heat shock proteins including HSPB8 (HSP22), HSPB2 (MKBP) and HSPB1 (HSP27). Unlike the canonical small HSPs HSPB1 and HSPB5, HSPB7 does not promote refolding of denatured substrates; instead it acts as a non-canonical chaperone/sequestrase that binds and sequesters aggregation-prone proteins (e.g. polyglutamine-expanded and filamin clients), suppressing their aggregation. HSPB7 localizes to the cytoplasm and nucleus and constitutively resides in SC35 nuclear splicing speckles via its N-terminal region. It is implicated in cardiac biology and cardiomyopathy risk. 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; HSPB7 is directly documented in the nucleus and constitutively resides in SC35 nuclear splicing speckles. action: ACCEPT reason: Corroborated by direct experimental (IDA) evidence (PMID:19464326) and the UniProt subcellular-location record. supported_by: - reference_id: file:human/HSPB7/HSPB7-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19464326}. Nucleus' - 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; HSPB7 has a documented cytoplasmic pool in addition to its nuclear-speckle residence. action: ACCEPT reason: Corroborated by direct experimental (IDA) evidence (PMID:19464326) and the UniProt subcellular-location record. supported_by: - reference_id: file:human/HSPB7/HSPB7-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - 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 HSPB7 in the nucleus. supported_by: - reference_id: file:human/HSPB7/HSPB7-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/HSPB7/HSPB7-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0007507 label: heart development evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: InterPro-based electronic annotation to heart development, reflecting HSPB7's cardiac-enriched expression and family associations. No direct experimental demonstration of a role in heart morphogenesis for human HSPB7. action: KEEP_AS_NON_CORE reason: Plausible given the strong cardiac/cardiovascular expression of cvHsp, but derived from an InterPro-to-GO family rule rather than direct experimental evidence for this gene; retained as a non-core process. supported_by: - reference_id: PMID:10593960 supporting_text: selectively expressed in cardiovascular and insulin-sensitive tissues - term: id: GO:0015030 label: Cajal body evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: UniProt-SubCell-derived electronic localization to Cajal bodies, consistent with HSPB7's reported sub-nuclear localization to splicing-related nuclear bodies. action: KEEP_AS_NON_CORE reason: Supported by the UniProt subcellular-location record (Cajal body), but sub-nuclear body localization is peripheral to HSPB7's core chaperone/sequestrase function. supported_by: - reference_id: file:human/HSPB7/HSPB7-uniprot.txt supporting_text: Nucleus, Cajal body {ECO:0000269|PubMed:19464326} - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14594798 qualifier: enables review: summary: Demonstrates that HSPB7 (cvHSP) hetero-dimerizes with the small heat shock protein HSPB8 (HSP22) through a C-C interaction. The bare protein binding term is uninformative; the interaction is with a heat shock protein. action: MODIFY reason: Per curation guidelines, bare protein binding (GO:0005515) is uninformative. The documented partner here is the small HSP HSPB8, so the more informative MF is heat shock protein binding (GO:0031072). 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 an HSPB7-HSPB8 (Q9UJY1) interaction. The bare protein binding term is uninformative; the partner is a heat shock protein. action: MODIFY reason: Bare protein binding is uninformative. The WITH partner is HSPB8 (Q9UJY1), a small heat shock protein, so heat shock protein binding (GO:0031072) is the appropriate specific term. proposed_replacement_terms: - id: GO:0031072 label: heat shock protein binding supported_by: - reference_id: file:human/HSPB7/HSPB7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16189514 UniProtKB:Q9UJY1 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Yeast two-hybrid human interactome map capturing multiple HSPB7 interactions, including HSPB8 (Q9UJY1) and FLNA (P21333-2), alongside several non-chaperone partners. The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: This collapses many high-throughput interactions; while it includes the biologically meaningful HSPB8 and filamin partners (captured elsewhere as heat shock protein binding and filamin binding), the bare term records genuine interactions but is not itself an informative molecular function. supported_by: - reference_id: file:human/HSPB7/HSPB7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956 UniProtKB:P21333-2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: Interactome (BioPlex-type) screen capturing an HSPB7-FLNA (P21333-2) interaction, consistent with HSPB7's documented filamin binding. The bare protein binding term is uninformative. action: MODIFY reason: Bare protein binding is uninformative. The WITH partner is the filamin FLNA (P21333-2), and HSPB7's filamin binding is experimentally established, so filamin binding (GO:0031005) is the appropriate specific molecular function. proposed_replacement_terms: - id: GO:0031005 label: filamin binding supported_by: - reference_id: file:human/HSPB7/HSPB7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442 UniProtKB:P21333-2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Reference binary interactome map capturing many HSPB7 interactions, including the co-chaperone BAG3 (O95817), HSPB8 (Q9UJY1) and FLNA (P21333-2). The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: A large set of binary interactions collapsed under the uninformative bare term; the functionally salient partners (HSPB8, BAG3, filamin) are better captured as heat shock protein binding and filamin binding. Retained as non-core because it records genuine interactions. supported_by: - reference_id: file:human/HSPB7/HSPB7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:O95817 - term: id: GO:0015629 label: actin cytoskeleton evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Ensembl-ortholog-based electronic localization to the actin cytoskeleton, consistent with HSPB7's binding to the actin-crosslinker filamin. action: KEEP_AS_NON_CORE reason: Plausible given the experimentally established filamin binding, but supported only by ortholog-based electronic inference; retained as a non-core localization. supported_by: - reference_id: file:human/HSPB7/HSPB7-uniprot.txt supporting_text: Interacts with C-terminal domain of actin-binding protein 280. - term: id: GO:0031005 label: filamin binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: HSPB7 binds alpha-filamin (actin-binding protein 280) through its alpha-crystallin domain; this is a directly documented molecular function of cvHsp, although the GOA annotation here is by ortholog-based electronic inference. action: ACCEPT reason: Filamin binding is experimentally established for human cvHsp (PMID:10593960), making this electronic annotation correct and a core molecular function. supported_by: - reference_id: PMID:10593960 supporting_text: cvHsp interacted in both yeast two-hybrid and immunoprecipitation experiments with alpha-filamin or actin-binding protein 280 - reference_id: file:human/HSPB7/HSPB7-uniprot.txt supporting_text: Interacts with C-terminal domain of actin-binding protein 280. - 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; HSPB7 constitutively resides in SC35 splicing speckles. action: ACCEPT reason: IDA-supported nuclear localization, consistent with UniProt and the SC35-speckle residence. supported_by: - reference_id: PMID:19464326 supporting_text: HSPB7 constitutively localized to SC35 splicing speckles, driven by its - 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 a cytoplasmic pool of HSPB7. action: ACCEPT reason: IDA-supported cytoplasmic localization from the HSPB-family subcellular-distribution survey. supported_by: - reference_id: file:human/HSPB7/HSPB7-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:19464326} - term: id: GO:0006986 label: response to unfolded protein evidence_type: TAS original_reference_id: PMID:10593960 qualifier: involved_in review: summary: HSPB7 (cvHsp) is a small stress protein of the sHSP family. It participates in the cellular response to proteotoxic stress, although notably by sequestering aggregation-prone clients rather than by promoting refolding. action: ACCEPT reason: Membership in the stress-responsive small heat shock protein family supports this process annotation; cvHsp was characterized as a small stress protein. supported_by: - reference_id: PMID:10593960 supporting_text: a novel small stress protein of 170 amino acids that we named cvHsp - term: id: GO:0008016 label: regulation of heart contraction evidence_type: TAS original_reference_id: PMID:10593960 qualifier: involved_in review: summary: Annotation derived from the original cvHsp characterization, reflecting its high cardiac expression and filamin interaction. A direct role in regulating heart contraction is inferred rather than demonstrated. action: KEEP_AS_NON_CORE reason: Plausible given cardiac-restricted expression and filamin (cytoskeletal) binding, but the contractile-regulation role is indirect/inferential; retained as non-core. supported_by: - reference_id: PMID:10593960 supporting_text: selectively expressed in cardiovascular and insulin-sensitive tissues 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:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: PMID:10593960 title: Identification and characterization of cvHsp. A novel human small stress protein selectively expressed in cardiovascular and insulin-sensitive tissues. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Cached publications/PMID_10593960.md title matches; anchored to GOA as a TAS source for GO:0006986 (response to unfolded protein) and GO:0008016 (regulation of heart contraction). Identifies cvHsp/HSPB7 and its alpha-filamin binding, supporting core_function GO:0031005 (filamin binding). Cited in core_functions supported_by." findings: - statement: Identified cvHsp/HSPB7 as a 170-aa small stress protein highly expressed in heart and skeletal muscle that binds the C-terminal tail of alpha-filamin (actin-binding protein 280) via residues 56-119. reference_section_type: RESULTS - id: PMID:14594798 title: Interaction of human HSP22 (HSPB8) with other small heat shock proteins. findings: - statement: HSPB8 (HSP22) hetero-dimerizes with cvHSP (HSPB7) through a C-terminal to C-terminal interaction, and also interacts with HSPB2 (MKBP) and HSPB1 (HSP27), defining the small-HSP hetero-oligomer network. reference_section_type: RESULTS - id: PMID:16189514 title: Towards a proteome-scale map of the human protein-protein interaction network. findings: [] - id: PMID:19464326 title: HSPB7 is a SC35 speckle resident small heat shock protein. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Cached publications/PMID_19464326.md title matches; anchored to GOA as the IDA source for GO:0005634 (nucleus) and GO:0005737 (cytoplasm). Shows HSPB7 is a non-canonical sHSP that does not support substrate refolding, directly informing the holdase/sequestrase core function. Cited in core_functions supported_by." findings: - statement: HSPB7 constitutively localizes to SC35 nuclear splicing speckles driven by its N-terminus and, unlike HSPB1/HSPB5, does not support refolding of heat-denatured substrates, indicating a non-canonical chaperone role. reference_section_type: RESULTS - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: file:human/HSPB7/HSPB7-uniprot.txt title: UniProt entry Q9UBY9 (HSPB7_HUMAN), Heat shock protein beta-7 (cvHsp) findings: - statement: Cardiovascular small heat shock protein; binds actin-binding protein 280 (filamin); interacts with HSPB8 and BAG3; cytoplasm, nucleus and SC35 splicing speckles; heart/skeletal-muscle enriched. reference_section_type: OTHER core_functions: - description: Non-canonical small heat shock protein that binds aggregation-prone client proteins and small-HSP partners (e.g. HSPB8, HSPB2, HSPB1) and sequesters them to suppress aggregation, without promoting substrate refolding. molecular_function: id: GO:0051082 label: unfolded protein binding locations: - id: GO:0005737 label: cytoplasm - id: GO:0005634 label: nucleus supported_by: - reference_id: PMID:19464326 supporting_text: HSPB7 did not support refolding - reference_id: PMID:14594798 supporting_text: HSP22 interacts with itself, cvHSP (HSPB7), MKBP (HSPB2) and HSP27 - description: Binding to the actin-crosslinking protein filamin (alpha-filamin / actin-binding protein 280) via the alpha-crystallin domain, linking HSPB7 to the cardiac/muscle cytoskeleton. molecular_function: id: GO:0031005 label: filamin binding locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:10593960 supporting_text: cvHsp interacted in both yeast two-hybrid and immunoprecipitation experiments with alpha-filamin or actin-binding protein 280 proposed_new_terms: [] suggested_questions: - question: What is the molecular mechanism by which HSPB7 suppresses aggregation of clients such as polyglutamine-expanded proteins and mutant filamin without supporting their refolding? - question: Does HSPB7's residence in SC35 splicing speckles reflect a role in RNA/splicing biology, or is it a storage/sequestration site distinct from its cytoskeletal function? - question: How do HSPB7 hetero-oligomers with HSPB8/BAG3 contribute to chaperone-assisted selective autophagy in cardiomyocytes? suggested_experiments: - description: In vitro aggregation-suppression assays comparing HSPB7 with canonical HSPB1/HSPB5 on amyloidogenic and polyQ substrates, paired with refolding assays to confirm holdase/sequestrase (non-foldase) behavior. - description: Domain-swap and point-mutation analysis of the HSPB7 N-terminal region (1-71) to dissect SC35-speckle targeting versus client sequestration. - description: Cardiomyocyte HSPB7 knockout/knock-in models to test effects on filamin handling, proteostasis, and contractile function.