id: Q0VDF9 gene_symbol: HSPA14 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: HSPA14 (Heat shock 70 kDa protein 14, also called HSP70L1 / HSP70-like protein 1) is an atypical, divergent member of the HSP70 family and the Hsp70/DnaK-type subunit of the mammalian ribosome-associated complex (RAC). RAC is a stable cytosolic heterodimer of HSPA14 and the Hsp40/DnaJ-type co-chaperone DNAJC2 (MPP11) that docks at the ribosomal exit tunnel, where it engages emerging nascent polypeptide chains and assists their co-translational ('de novo') folding. Within RAC, HSPA14 provides the nucleotide-binding/substrate-binding HSP70 module while DNAJC2 stimulates its ATPase activity; the complex couples the chaperone cycle to ongoing translation rather than acting as an autonomous stress-induced refoldase. HSPA14 is cytosolic and ribosome-associated, and has additionally been described as an immunoadjuvant capable of activating antigen-presenting cells. existing_annotations: - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic (IBA) nuclear localization transferred from the broader HSP70 family. HSPA14 is documented as cytosolic and ribosome-associated; there is no experimental support for it acting in the nucleus. action: MARK_AS_OVER_ANNOTATED reason: This family-level PANTHER transfer reflects nuclear roles of canonical HSP70s, not HSPA14. UniProt records the subcellular location as cytoplasm/cytosol only, consistent with its dedicated role as a ribosome-associated RAC subunit. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0005886 label: plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic (IBA) plasma-membrane localization transferred from HSP70 family members. HSPA14 is a cytosolic ribosome-associated chaperone with no evidence of acting at the plasma membrane. action: MARK_AS_OVER_ANNOTATED reason: Family-level transfer inconsistent with HSPA14's documented cytosolic localization; no experimental support for a plasma-membrane site of action. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: HSPA14 possesses an HSP70 nucleotide-binding domain and hydrolyzes ATP; within RAC its ATPase activity is stimulated by the J-protein DNAJC2. ATP hydrolysis is central to the HSP70 chaperone cycle that HSPA14 contributes to. action: ACCEPT reason: Consistent with the HSP70 fold and explicitly supported by UniProt, which states DNAJC2 stimulates HSPA14's ATPase activity within the RAC complex. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: In the RAC complex, binds to the nascent polypeptide chain, while DNAJC2 stimulates its ATPase activity. - term: id: GO:0031072 label: heat shock protein binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: HSPA14 forms a stable heterodimer with the Hsp40/J-domain protein DNAJC2 (MPP11) within RAC, consistent with binding a heat shock/chaperone family protein. action: ACCEPT reason: The HSPA14-DNAJC2 interaction is experimentally established (RAC heterodimer); binding its J-protein partner is part of HSPA14's co-chaperone module function. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2 - reference_id: PMID:16002468 supporting_text: Purification of MPP11 revealed that it forms a stable complex with Hsp70L1, a distantly related - term: id: GO:0044183 label: protein folding chaperone evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: As the HSP70 subunit of RAC, HSPA14 acts as a chaperone that binds nascent polypeptides and assists their folding co-translationally. This is its core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION (RAC binds and maintains nascent polypeptides in a folding-competent state) and by the RAC characterization in PMID:16002468. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: a complex involved in folding or maintaining nascent polypeptides in a folding- - term: id: GO:0005829 label: cytosol evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic cytosolic localization, corroborated by direct experimental evidence (IDA) and UniProt. HSPA14 acts in the cytosol as part of RAC. action: ACCEPT reason: Agrees with UniProt subcellular location and IDA evidence (PMID:16002468, PMID:21231916); cytosol is the genuine compartment of HSPA14 action. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0042026 label: protein refolding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Protein refolding is a hallmark of canonical stress-induced HSP70s. HSPA14 is specialized for co-translational ('de novo') folding of nascent chains as a RAC subunit, not for stress-induced refolding of denatured proteins. action: MARK_AS_OVER_ANNOTATED reason: Family-level transfer of the canonical HSP70 refolding role; HSPA14's documented activity is co-translational nascent-chain folding within RAC, better captured by GO:0051083. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: a complex involved in folding or maintaining nascent polypeptides in a folding- - term: id: GO:0005840 label: ribosome evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: colocalizes_with review: summary: HSPA14/RAC associates with ribosomes at the exit tunnel; ribosome colocalization is directly demonstrated and phylogenetically inferred. action: ACCEPT reason: Corroborated by IDA evidence in PMID:16002468 (RAC associates with ribosomes); central to its co-translational function. supported_by: - reference_id: PMID:16002468 supporting_text: MPP11 is localized to the cytosol and associates with ribosomes - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro-based annotation of ATP binding via the HSP70 nucleotide-binding domain. HSPA14 contains a canonical HSP70 NBD. action: ACCEPT reason: Consistent with the HSP70 fold and the nucleotide-dependent chaperone cycle; ATP binding underlies the ATPase activity stimulated by DNAJC2. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: 'SIMILARITY: Belongs to the heat shock protein 70 family.' - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated (UniProt SubCell) cytosolic localization, redundant with and consistent with the experimentally supported cytosol annotations. action: ACCEPT reason: Agrees with stronger IDA/IBA evidence and UniProt subcellular location for the same compartment. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro-based ATP hydrolysis annotation, redundant with the IBA ATPase annotation and consistent with the HSP70 NBD. action: ACCEPT reason: Same enzymatic activity as the IBA annotation; supported by the HSP70 fold and by DNAJC2 stimulation of HSPA14 ATPase activity. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: while DNAJC2 stimulates its ATPase activity. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: High-throughput IntAct interaction with NFAM1 (Q8NET5). Bare protein binding is uninformative, and NFAM1 is unrelated to HSPA14's chaperone function. action: KEEP_AS_NON_CORE reason: Isolated high-throughput interaction with a non-chaperone partner (NFAM1); uninformative protein binding term that does not reflect HSPA14's RAC/co-translational folding role. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: 'SIMILARITY: Belongs to the heat shock protein 70 family.' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex affinity-purification interactome capturing HSPA14 interactions including DNAJC2 (Q99543, its RAC partner). The DNAJC2 interaction is biologically meaningful; bare protein binding itself is uninformative. action: MODIFY reason: The biologically relevant partner here is DNAJC2 (Q99543), HSPA14's J-protein partner in RAC; this is more precisely captured as heat shock protein binding. proposed_replacement_terms: - id: GO:0031072 label: heat shock protein binding supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 qualifier: enables review: summary: IntAct interaction with DNAJC2 (Q99543), the RAC J-protein partner. Bare protein binding is uninformative but the partner is HSPA14's key chaperone partner. action: MODIFY reason: The WITH partner is DNAJC2 (Q99543), HSPA14's RAC partner; the interaction is more precisely captured as heat shock protein binding. proposed_replacement_terms: - id: GO:0031072 label: heat shock protein binding supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Multimodal cell-maps interactome capturing an HSPA14-DNAJC2 (Q99543) interaction. Bare protein binding is uninformative; the partner is the RAC J-protein. action: MODIFY reason: The WITH partner DNAJC2 (Q99543) is HSPA14's RAC partner; more precisely captured as heat shock protein binding. proposed_replacement_terms: - id: GO:0031072 label: heat shock protein binding supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2 - term: id: GO:0006457 label: protein folding evidence_type: NAS original_reference_id: PMID:16002468 qualifier: involved_in review: summary: ComplexPortal NAS annotation of protein folding for the RAC complex. HSPA14 participates in folding nascent chains; the more specific process is co-translational folding. action: KEEP_AS_NON_CORE reason: Protein folding is the broad outcome of the RAC chaperone module; retained as a non-core process, with the precise process captured by GO:0051083. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: a complex involved in folding or maintaining nascent polypeptides in a folding- - term: id: GO:0101031 label: protein folding chaperone complex evidence_type: IPI original_reference_id: PMID:16002468 qualifier: part_of review: summary: HSPA14 is part of the ribosome-associated complex (RAC), a folding chaperone complex with DNAJC2. This is a precise and accurate complex annotation. action: ACCEPT reason: Directly supported by the RAC heterodimer characterization in PMID:16002468 and UniProt SUBUNIT; RAC is exactly a protein folding chaperone complex. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: Component of ribosome-associated complex (RAC), a heterodimer - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: High-throughput membrane-proteome detection. HSPA14 is a cytosolic, ribosome-associated chaperone; any membrane association is peripheral, not a core localization. action: KEEP_AS_NON_CORE reason: HDA detection in a membrane proteome; peripheral to HSPA14's documented cytosolic/ribosome-associated site of action. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:21231916 qualifier: located_in review: summary: Direct experimental evidence for cytosolic localization, consistent with HSPA14's role as a cytosolic ribosome-associated chaperone. action: ACCEPT reason: IDA-supported cytosol annotation agreeing with UniProt and other cytosol evidence; the genuine compartment of HSPA14. supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16002468 qualifier: enables review: summary: IPI interaction with DNAJC2 (Q99543) from the original RAC characterization. Bare protein binding is uninformative, but this is HSPA14's defining RAC partner. action: MODIFY reason: The WITH partner DNAJC2 (Q99543) is the J-protein partner forming RAC with HSPA14; more precisely captured as heat shock protein binding. proposed_replacement_terms: - id: GO:0031072 label: heat shock protein binding supported_by: - reference_id: PMID:16002468 supporting_text: Purification of MPP11 revealed that it forms a stable complex with Hsp70L1, a distantly related - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:16002468 qualifier: located_in review: summary: Direct experimental cytosolic localization from the RAC characterization paper, consistent with all other cytosol evidence. action: ACCEPT reason: IDA cytosol annotation from PMID:16002468 (MPP11/HSPA14 localized to the cytosol); the genuine compartment of HSPA14. supported_by: - reference_id: PMID:16002468 supporting_text: MPP11 is localized to the cytosol and associates with ribosomes - term: id: GO:0005840 label: ribosome evidence_type: IDA original_reference_id: PMID:16002468 qualifier: colocalizes_with review: summary: Direct experimental evidence that HSPA14/RAC associates with ribosomes and comigrates with polysomes. Central to its co-translational role. action: ACCEPT reason: IDA-supported ribosome colocalization from the RAC characterization; HSPA14 acts at the ribosomal exit tunnel. supported_by: - reference_id: PMID:16002468 supporting_text: MPP11 is localized to the cytosol and associates with ribosomes - term: id: GO:0051083 label: '''de novo'' cotranslational protein folding' evidence_type: TAS original_reference_id: PMID:16002468 qualifier: involved_in review: summary: HSPA14, as the HSP70 subunit of RAC, assists co-translational folding of nascent polypeptides at the ribosome. This is the precise core biological process for HSPA14. action: ACCEPT reason: Directly supported by the RAC characterization (cotranslational interaction with nascent polypeptides) and UniProt FUNCTION; the most specific and accurate BP for HSPA14. supported_by: - reference_id: PMID:16002468 supporting_text: Soluble Hsp70 homologs cotranslationally interact with nascent polypeptides in - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: a complex involved in folding or maintaining nascent polypeptides in a folding- 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 based on UniProtKB Subcellular Location vocabulary mapping findings: [] - id: PMID:16002468 title: The chaperones MPP11 and Hsp70L1 form the mammalian ribosome-associated complex. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Cached publications/PMID_16002468.md title matches exactly; richly anchored in GOA as the source for GO:0005840 (ribosome, IDA), GO:0005829 (cytosol, IDA), GO:0051083 ('de novo' cotranslational protein folding, TAS), GO:0006457 (protein folding, NAS) and GO:0101031 (protein folding chaperone complex). The defining paper establishing the HSPA14/DNAJC2 RAC; directly supports both core functions. Cited in core_functions supported_by." findings: - statement: Human MPP11 (DNAJC2) forms a stable heterodimeric ribosome-associated complex (RAC) with Hsp70L1 (HSPA14), the mammalian counterpart of yeast Ssz1p/zuotin, functioning in co-translational folding at the ribosome. reference_section_type: ABSTRACT - statement: HSPA14/RAC is cytosolic and associates with ribosomes, consistent with action at the ribosomal exit tunnel. reference_section_type: RESULTS - id: PMID:19946888 title: Defining the membrane proteome of NK cells. findings: [] - id: PMID:21231916 title: The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: [] - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: file:human/HSPA14/HSPA14-uniprot.txt title: UniProt entry Q0VDF9 (HSP7E_HUMAN), Heat shock 70 kDa protein 14 / HSP70L1 findings: - statement: HSPA14 is the Hsp70/DnaK-type subunit of the ribosome-associated complex (RAC), a heterodimer with the Hsp40/DnaJ-type co-chaperone DNAJC2; it binds nascent polypeptides while DNAJC2 stimulates its ATPase activity. It is cytosolic and belongs to the HSP70 family. reference_section_type: OTHER core_functions: - description: Hsp70/DnaK-type chaperone subunit of the ribosome-associated complex (RAC) that binds nascent polypeptide chains at the ribosome and, with its J-protein partner DNAJC2, assists their co-translational folding in an ATP-dependent manner. molecular_function: id: GO:0044183 label: protein folding chaperone locations: - id: GO:0005829 label: cytosol - id: GO:0005840 label: ribosome supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: a complex involved in folding or maintaining nascent polypeptides in a folding- - reference_id: PMID:16002468 supporting_text: Soluble Hsp70 homologs cotranslationally interact with nascent polypeptides in - description: ATP binding and DNAJC2-stimulated ATP hydrolysis through the HSP70 nucleotide-binding domain, driving the RAC chaperone cycle on nascent chains. molecular_function: id: GO:0016887 label: ATP hydrolysis activity locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/HSPA14/HSPA14-uniprot.txt supporting_text: while DNAJC2 stimulates its ATPase activity. proposed_new_terms: [] suggested_questions: - question: Does human HSPA14 retain measurable intrinsic ATPase activity, or is it (like yeast Ssz1p) an atypical HSP70 whose nucleotide cycle is functionally subordinate to stimulating the downstream ribosome-bound HSP70 (HSPA8/Ssb-type)? - question: What is the nascent-chain client spectrum of human RAC, and does HSPA14/DNAJC2 show substrate selectivity among co-translationally folding proteins? - question: Is the reported immunoadjuvant/dendritic-cell-activating activity of HSP70L1 a genuine extracellular function or an artifact of recombinant protein preparations? suggested_experiments: - description: Reconstitute human RAC (HSPA14 + DNAJC2) in vitro and measure ATPase activity alone and in the presence of ribosomes and a ribosome-bound HSP70 to test whether HSPA14 stimulates the partner HSP70 ATPase, as in yeast. - description: Selective ribosome profiling or nascent-chain crosslinking after HSPA14 knockdown to define the co-translational client repertoire and folding defects. - description: Domain-swap and point-mutation analysis of the HSPA14 nucleotide-binding and substrate-binding domains to map the determinants of DNAJC2 binding and nascent-chain engagement.