HSPA14, also called Hsp70L1, is an atypical HSP70-family subunit of the mammalian ribosome-associated complex (mRAC). It forms a stable heterodimer with the J-domain protein DNAJC2/MPP11 in the cytosol. mRAC associates with ribosomes and promotes recruitment and activity of a separate Hsp70 chaperone on nascent polypeptides, supporting cotranslational protein folding. ATP binding to HSPA14 supports this cofactor function, whereas its own ATP hydrolysis is dispensable in yeast complementation and remains biochemically unresolved because measured turnover is close to background. HSPA14 has also been detected in a membrane proteomics study, and recombinant Hsp70L1 has immunostimulatory activity in antigen-presenting-cell experiments.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | UNDECIDED | Summary: Additional nucleus capacity remains unresolved. Reason: Predominant cytosolic ribosome-associated function is not exclusive. The current tree contains the nuclear IBD on the exact target path. DNAJC2 chromatin activity does not itself establish HSPA14 nuclear activity. A focused report is pending; the absence of a target assay alone is not a reason to reject the ancestral assertion. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN002500132 UNRESOLVED The current tree contains the nuclear IBD on the exact target path. DNAJC2 chromatin activity does not itself establish HSPA14 nuclear activity. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | UNDECIDED | Summary: Additional plasma membrane capacity remains unresolved. Reason: Predominant cytosolic ribosome-associated function is not exclusive. The original plasma-membrane IBA cites PTN002500132, but that GO term was not recovered on the current target path. This is a source-version discrepancy, not experimental evidence of absence. Membrane HDA PMID:19946888 does not by itself resolve plasma-membrane activity. A focused report is pending; the absence of a target assay alone is not a reason to reject the ancestral assertion. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN002500132 UNRESOLVED The original plasma-membrane IBA cites PTN002500132, but that GO term was not recovered on the current target path. This is a source-version discrepancy, not experimental evidence of absence. Membrane HDA PMID:19946888 does not by itself resolve plasma-membrane activity. |
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | UNDECIDED | Summary: Intrinsic HSPA14 ATP hydrolysis is not settled by the available direct assay. Reason: Full PMID:21245388 measured purified mRAC turnover at approximately0.01 ATP/min, above binding-defective mRAC-LKA and MPP11 but close to background; the authors explicitly withheld a definitive ATPase conclusion. ATP-binding mutants and hydrolysis-site mutants separate nucleotide binding from hydrolysis dependence. Stimulation of a separate Hsp70 by mRAC must not be described as DNAJC2 stimulation of HSPA14 itself. The ancestral IBD is real, but target biochemical uncertainty warrants adjudication. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000452648 UNRESOLVED Actual target ancestry verified; near-background target assay does not establish either robust catalysis or complete loss. Supporting Evidence: PMID:21245388 Based on the currently available data, the question of whether Hsp70L1 can hydrolyze ATP cannot be conclusively answered. PMID:21245388 the function of mRAC depends on ATP binding to Hsp70L1 but does not depend on ATP hydrolysis. |
| GO:0031072 heat shock protein binding | IBA GO_REF:0000033 | ACCEPT | 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. Reason: The HSPA14-DNAJC2 interaction is experimentally established (RAC heterodimer); binding its J-protein partner is part of HSPA14's co-chaperone module function. Supporting Evidence: file:human/HSPA14/HSPA14-uniprot.txt heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2 PMID:16002468 Purification of MPP11 revealed that it forms a stable complex with Hsp70L1, a distantly related |
| GO:0044183 protein folding chaperone | IBA GO_REF:0000033 | ACCEPT | Summary: HSPA14 contributes to cotranslational protein folding through the mRAC chaperone complex. Reason: The actual ancestral folding inference is consistent with target mRAC assembly and the 2011 demonstration that the complex recruits and stimulates Hsp70 on nascent chains. Direct nascent-chain binding by the HSPA14 subunit was proposed, not separately proven; its cofactor contribution to the folding machinery is supported. Supporting Evidence: PMID:21245388 Thus, mRAC was involved in the recruitment specifically of Hsp70 to nascent chains. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic cytosolic localization, corroborated by direct experimental evidence (IDA) and UniProt. HSPA14 acts in the cytosol as part of RAC. Reason: Agrees with UniProt subcellular location and IDA evidence (PMID:16002468, PMID:21231916); cytosol is the genuine compartment of HSPA14 action. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002500132 SUPPORTS TRANSFER Actual target ancestry verified. Q0VDF9 in the source set reflects its own experimental grounding and is not circularity. Supporting Evidence: file:human/HSPA14/HSPA14-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0042026 protein refolding | IBA GO_REF:0000033 | UNDECIDED | Summary: Additional protein refolding capacity remains unresolved. Reason: Predominant cytosolic ribosome-associated function is not exclusive. The refolding IBD is on the actual target path. The yeast SSZ1 loss node is outside this path. Full target-specific assays in PMID:21231916 and possible alternative substrates/cofactors require adjudication; predominant cotranslational work does not exclude refolding. A focused report is pending; the absence of a target assay alone is not a reason to reject the ancestral assertion. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000452648 UNRESOLVED The refolding IBD is on the actual target path. The yeast SSZ1 loss node is outside this path. Full target-specific assays in PMID:21231916 and possible alternative substrates/cofactors require adjudication; predominant cotranslational work does not exclude refolding. |
| GO:0005840 ribosome | IBA GO_REF:0000033 | ACCEPT | Summary: HSPA14/RAC associates with ribosomes at the exit tunnel; ribosome colocalization is directly demonstrated and phylogenetically inferred. Reason: Corroborated by IDA evidence in PMID:16002468 (RAC associates with ribosomes); central to its co-translational function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001065003 SUPPORTS TRANSFER Actual target ancestry verified. Q0VDF9 in the source set reflects its own experimental grounding and is not circularity. Supporting Evidence: PMID:16002468 MPP11 is localized to the cytosol and associates with ribosomes |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding directly supports HSPA14 cofactor function. Reason: Full PMID:21245388 demonstrates ATP analog cross-linking to Hsp70L1 and loss of effective complementation/cochaperone stimulation with the ATP-binding-defective LKA mutant. This is distinct from, and does not require accepting, intrinsic hydrolysis. Supporting Evidence: PMID:21245388 the function of mRAC depends on ATP binding to Hsp70L1 but does not depend on ATP hydrolysis. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Automated (UniProt SubCell) cytosolic localization, redundant with and consistent with the experimentally supported cytosol annotations. Reason: Agrees with stronger IDA/IBA evidence and UniProt subcellular location for the same compartment. Supporting Evidence: file:human/HSPA14/HSPA14-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | UNDECIDED | Summary: Intrinsic HSPA14 ATP hydrolysis is not settled by the available direct assay. Reason: Full PMID:21245388 measured purified mRAC turnover at approximately0.01 ATP/min, above binding-defective mRAC-LKA and MPP11 but close to background; the authors explicitly withheld a definitive ATPase conclusion. ATP-binding mutants and hydrolysis-site mutants separate nucleotide binding from hydrolysis dependence. Stimulation of a separate Hsp70 by mRAC must not be described as DNAJC2 stimulation of HSPA14 itself. The ancestral IBD is real, but target biochemical uncertainty warrants adjudication. Supporting Evidence: PMID:21245388 Based on the currently available data, the question of whether Hsp70L1 can hydrolyze ATP cannot be conclusively answered. PMID:21245388 the function of mRAC depends on ATP binding to Hsp70L1 but does not depend on ATP hydrolysis. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Bare protein binding does not identify a useful molecular activity. Reason: The source interaction with NFAM1 is retained as an experimental interaction observation, but the broad GO:0005515 label adds no informative molecular function. Removal is a term-specific curation choice, not a claim that the interaction is false or impossible because it is outside mRAC. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | 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. 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 replacements: heat shock protein binding Supporting Evidence: file:human/HSPA14/HSPA14-uniprot.txt heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | 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. Reason: The WITH partner is DNAJC2 (Q99543), HSPA14's RAC partner; the interaction is more precisely captured as heat shock protein binding. Proposed replacements: heat shock protein binding Supporting Evidence: file:human/HSPA14/HSPA14-uniprot.txt heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: Multimodal cell-maps interactome capturing an HSPA14-DNAJC2 (Q99543) interaction. Bare protein binding is uninformative; the partner is the RAC J-protein. Reason: The WITH partner DNAJC2 (Q99543) is HSPA14's RAC partner; more precisely captured as heat shock protein binding. Proposed replacements: heat shock protein binding Supporting Evidence: file:human/HSPA14/HSPA14-uniprot.txt heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2 |
| GO:0006457 protein folding | NAS PMID:16002468 The chaperones MPP11 and Hsp70L1 form the mammalian ribosome... | ACCEPT | Summary: Protein folding is a valid broad description of the core mRAC role. Reason: HSPA14 contributes to the ribosome-associated chaperone complex that recruits and stimulates Hsp70 at nascent chains. The more specific cotranslational annotation does not make its protein-folding parent noncore. Supporting Evidence: PMID:21245388 Thus, mRAC was involved in the recruitment specifically of Hsp70 to nascent chains. |
| GO:0101031 protein folding chaperone complex | IPI PMID:16002468 The chaperones MPP11 and Hsp70L1 form the mammalian ribosome... | ACCEPT | Summary: HSPA14 is part of the ribosome-associated complex (RAC), a folding chaperone complex with DNAJC2. This is a precise and accurate complex annotation. Reason: Directly supported by the RAC heterodimer characterization in PMID:16002468 and UniProt SUBUNIT; RAC is exactly a protein folding chaperone complex. Supporting Evidence: file:human/HSPA14/HSPA14-uniprot.txt Component of ribosome-associated complex (RAC), a heterodimer |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: High-throughput membrane-proteome detection. HSPA14 is a cytosolic, ribosome-associated chaperone; any membrane association is peripheral, not a core localization. Reason: HDA detection in a membrane proteome; peripheral to HSPA14's documented cytosolic/ribosome-associated site of action. Supporting Evidence: file:human/HSPA14/HSPA14-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: Direct experimental evidence for cytosolic localization, consistent with HSPA14's role as a cytosolic ribosome-associated chaperone. Reason: IDA-supported cytosol annotation agreeing with UniProt and other cytosol evidence; the genuine compartment of HSPA14. Supporting Evidence: file:human/HSPA14/HSPA14-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005515 protein binding | IPI PMID:16002468 The chaperones MPP11 and Hsp70L1 form the mammalian ribosome... | MODIFY | Summary: IPI interaction with DNAJC2 (Q99543) from the original RAC characterization. Bare protein binding is uninformative, but this is HSPA14's defining RAC partner. Reason: The WITH partner DNAJC2 (Q99543) is the J-protein partner forming RAC with HSPA14; more precisely captured as heat shock protein binding. Proposed replacements: heat shock protein binding Supporting Evidence: PMID:16002468 Purification of MPP11 revealed that it forms a stable complex with Hsp70L1, a distantly related |
| GO:0005829 cytosol | IDA PMID:16002468 The chaperones MPP11 and Hsp70L1 form the mammalian ribosome... | ACCEPT | Summary: Direct experimental cytosolic localization from the RAC characterization paper, consistent with all other cytosol evidence. Reason: IDA cytosol annotation from PMID:16002468 (MPP11/HSPA14 localized to the cytosol); the genuine compartment of HSPA14. Supporting Evidence: PMID:16002468 MPP11 is localized to the cytosol and associates with ribosomes |
| GO:0005840 ribosome | IDA PMID:16002468 The chaperones MPP11 and Hsp70L1 form the mammalian ribosome... | ACCEPT | Summary: Direct experimental evidence that HSPA14/RAC associates with ribosomes and comigrates with polysomes. Central to its co-translational role. Reason: IDA-supported ribosome colocalization from the RAC characterization; HSPA14 acts at the ribosomal exit tunnel. Supporting Evidence: PMID:16002468 MPP11 is localized to the cytosol and associates with ribosomes |
| GO:0051083 'de novo' cotranslational protein folding | TAS PMID:16002468 The chaperones MPP11 and Hsp70L1 form the mammalian ribosome... | ACCEPT | Summary: HSPA14 contributes to cotranslational protein folding through the mRAC chaperone complex. Reason: The actual ancestral folding inference is consistent with target mRAC assembly and the 2011 demonstration that the complex recruits and stimulates Hsp70 on nascent chains. Direct nascent-chain binding by the HSPA14 subunit was proposed, not separately proven; its cofactor contribution to the folding machinery is supported. Supporting Evidence: PMID:21245388 Thus, mRAC was involved in the recruitment specifically of Hsp70 to nascent chains. |
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Download this section (compressed HTML)Q: Does intrinsic HSPA14 ATP turnover exceed background under physiological cofactors and substrate conditions, given the inconclusive0.01 ATP/min mRAC measurement in PMID:21245388? ATP binding and stimulation of separate Hsp70 are already established.
Q: What is the nascent-chain client spectrum of human RAC, and does HSPA14/DNAJC2 show substrate selectivity among co-translationally folding proteins?
Q: Is the reported immunoadjuvant/dendritic-cell-activating activity of HSP70L1 a genuine extracellular function or an artifact of recombinant protein preparations?
Experiment: 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.
Experiment: Selective ribosome profiling or nascent-chain crosslinking after HSPA14 knockdown to define the co-translational client repertoire and folding defects.
Experiment: 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.
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