HSPA14 (HSP70L1 / HSP70-like protein 1) — research notes

UniProt: Q0VDF9 (HSP7E_HUMAN), 509 aa. Gene synonyms HSP60, HSP70L1.

Core identity

HSP70-family protein and the Hsp70/DnaK-type subunit of the mammalian
ribosome-associated complex (RAC), a heterodimer with the Hsp40/DnaJ-type
co-chaperone DNAJC2 (MPP11). RAC acts at the ribosomal exit tunnel to assist
co-translational folding of nascent polypeptides.

• [file:human/HSPA14/HSPA14-uniprot.txt "FUNCTION: Component of the ribosome-associated complex (RAC), a complex involved in folding or maintaining nascent polypeptides in a folding-competent state. In the RAC complex, binds to the nascent polypeptide chain, while DNAJC2 stimulates its ATPase activity."]
• [file:human/HSPA14/HSPA14-uniprot.txt "SUBUNIT: Component of ribosome-associated complex (RAC), a heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2."]
• [file:human/HSPA14/HSPA14-uniprot.txt "SUBCELLULAR LOCATION: Cytoplasm, cytosol"]

RAC paper (PMID:16002468, Otto et al. 2005 PNAS)

Identified the mammalian RAC as MPP11(DNAJC2)/Hsp70L1.
- PMID:16002468
- PMID:16002468
- Important nuance: like its yeast counterpart Ssz1p, Hsp70L1 is an ATYPICAL Hsp70. In yeast RAC, Ssz1p/zuotin (RAC) act to stimulate the ATPase of the ribosome-bound Hsp70 Ssb1/2p; RAC itself is the co-chaperone module. So HSPA14's own ATP-hydrolysis "chaperone" role is not a canonical autonomous foldase.
- PMID:16002468
- HeLa immunofluorescence + rat liver fractionation: cytosolic, ribosome-associated.
- PMID:16002468

GO annotation review notes (goa.tsv)

• IBA nucleus / plasma membrane: family-level PANTHER transfers from canonical Hsp70s; no experimental support for HSPA14 in nucleus or PM. UniProt SUBCELLULAR LOCATION = cytoplasm/cytosol only. -> MARK_AS_OVER_ANNOTATED.
• IBA ATP hydrolysis activity / IEA ATP hydrolysis: HSP70 fold present; HSPA14 has nucleotide-binding domain. ATPase is stimulated by DNAJC2 in the RAC. Keep ATP binding (KW) and ATP hydrolysis as supported by fold + UniProt FUNCTION (DNAJC2 stimulates its ATPase activity). Core enzymatic-ish MF.
• IBA heat shock protein binding GO:0031072: as RAC subunit it binds DNAJC2 (an Hsp40); reasonable. ACCEPT non-core? It binds its J-protein partner. Keep as supporting.
• IBA / IEA protein folding chaperone (GO:0044183 / GO:0140662): HSPA14 functions in co-translational folding as part of RAC. GO:0044183 protein folding chaperone is a reasonable core-ish MF. But it is a co-chaperone module (with DNAJC2), assisting nascent-chain folding — keep as core MF (chaperone) with caveat.
• protein refolding GO:0042026 IBA: canonical Hsp70 refolding transferred from family; HSPA14 is specialized for co-translational (de novo) folding, not stress refolding. MARK_AS_OVER_ANNOTATED / KEEP_AS_NON_CORE.
• ribosome (GO:0005840) colocalizes_with IBA + IDA (PMID:16002468): directly shown. ACCEPT.
• cytosol GO:0005829 IBA/IEA/IDA (PMID:21231916, PMID:16002468): ACCEPT (IDA core localization).
• membrane GO:0016020 HDA (PMID:19946888): high-throughput membrane-proteome detection; HSPA14 is cytosolic/ribosome-associated; peripheral. KEEP_AS_NON_CORE.
• protein folding GO:0006457 NAS (ComplexPortal, PMID:16002468): RAC role. KEEP_AS_NON_CORE (downstream process of chaperone module).
• protein folding chaperone complex GO:0101031 part_of IPI (PMID:16002468): the RAC complex. ACCEPT (this is exactly RAC).
• 'de novo' cotranslational protein folding GO:0051083 TAS (PMID:16002468): the precise BP for RAC. ACCEPT as core process.
• protein binding IPI: partners DNAJC2 (Q99543) — informative (RAC partner) -> capture as Hsp70/chaperone binding; NFAM1 (Q8NET5) — HT interactome, not chaperone-related. Keep DNAJC2 ones meaningful, NFAM1 over-annotated.

Partner ID map: Q99543=DNAJC2(MPP11); Q8NET5=NFAM1.

Immunoadjuvant / DC activation

Hsp70L1 was reported to activate dendritic cells and act as a Th1 adjuvant
(PubMed:14592822, 15930317, 18851947). This is an applied/immunology property,
not a core GO molecular function; not in GOA. Noted, not annotated.

Core function synthesis

1. Hsp70/DnaK-type chaperone subunit of RAC — ATP-dependent, co-translational
   folding of nascent chains (GO:0044183 protein folding chaperone; process
   GO:0051083 de novo cotranslational protein folding; complex GO:0101031).
2. ATP binding / ATP hydrolysis (HSP70 NBD), stimulated by DNAJC2.

2026-09-21 full-gene re-review

All23 original source assertions preserved. Actual PTHR19375 v19 target leaf PTN002500131 is below ATPase/refolding IBD PTN000452648 and nuclear IBD PTN002500132. The SSZ1 loss node PTN001065099 is outside this path. The frozen plasma-membrane IBA cites PTN002500132 but the current path lacks that assertion; this is a version discrepancy, not a biological negative. Nuclear/PM/refolding exclusions based only on primary cytosol/mRAC specialization were replaced with uncertainty.

Full PMID:21245388 Methods/Results/Discussion distinguish ATP binding from catalysis: “the rate of ATP hydrolysis was only 0.01 ATP per min, which is very close to background hydrolysis.” Authors conclude “the question of whether Hsp70L1 can hydrolyze ATP cannot be conclusively answered.” Hydrolysis-site mutants complement yeast; binding-defective LKA does not. mRAC stimulates a separate Hsp70, not demonstrably its own Hsp70L1 subunit. Both ATPase rows now UNDECIDED, and description/core no longer assert the unsupported cycle. Full PMID:16002468 establishes the heterodimer and ribosome-associated contribution. Direct HSPA14 nascent-chain binding remains proposed.

All source interactions checked:33961781 includes NFAM1 and DNAJC2,35271311/40205054 include DNAJC2, supporting informative HSP-binding replacements. Bare28514442NFAM1 binding is removed as uninformative, not declared false. Broad foldingNAS restored to core. Generic membraneHDA remains contextual; membrane fraction is not proof of PM activity.

Existing SSZ1 ATPase OpenScientist output was read: its claim that metazoan HSPA14 was untested misses PMID:21245388. No target report existed in exact repository/global query checks. A distinct focused request includes this assay, the PMID:21231916 HSPA14 refolding figures, and secondary compartments. The author manuscript of PMID:21231916 was found at https://www.researchgate.net/publication/49752468_The_diverse_members_of_the_mammalian_HSP70_machine_show_distinct_chaperone-like_activities but its body font encoding and inaccessible PDF prevent reliable figure adjudication here. No NEW assertion added.

Recovery PR follow-up (2026-09-22)

Restored readable GO/PMID/PTN identifiers in curation prose. For DCV1, core
localization cites the recorded UniProt topology and SGD-attributed observation;
the unrelated Rim101 report sentence no longer supports plasma-membrane location.
For YAR1, unanswered report questions are not positive evidence. For SSQ1, the
located Nop1 association remains recorded while its generic binding label is removed.
The annotation changes apply only to the relevant gene; no inherited location is
rejected solely from its best-characterized compartment.