Affinage

HSPA12A

Heat shock 70 kDa protein 12A · UniProt O43301

Length
675 aa
Mass
75.0 kDa
Annotated
2026-04-28
20 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSPA12A is an atypical HSP70 family member that functions primarily as a scaffolding and adaptor protein, promoting the nuclear translocation of transcription-related partners (PKM2, PGC-1α, c-Myc, AP-1) and regulating protein stability through the ubiquitin-proteasome system (bridging p53 with USP10 for deubiquitination; facilitating HRD1-mediated CD147 degradation; enhancing Smurf1-dependent HIF-1α stabilization) (PMID:30455376, PMID:32332915, PMID:38219869, PMID:38421727, PMID:39277835). Through these interactions, HSPA12A controls glycolytic flux, lactate-driven protein lactylation (of HMGB1 and histones), and downstream transcriptional programs that govern macrophage polarization, pyroptosis, cardiac fibroblast activation, endothelial barrier integrity, angiogenesis, and tubular epithelial cell proliferation across liver, heart, kidney, and brain (PMID:37441587, PMID:35783189, PMID:34343936, PMID:39277835). HSPA12A also participates in a positive feedback loop with PPARγ to drive adipocyte differentiation and sustains hippocampal neurogenesis by maintaining cerebral lactate homeostasis through GSK3β inhibition (PMID:30742088, PMID:37580315). Alternative splicing of HSPA12A pre-mRNA is regulated by the PAK5–SRSF11 axis, with exon 2 retention yielding a transcript that stabilizes N-cadherin expression and promotes colorectal cancer metastasis (PMID:36394206).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2018 High

    Establishing that HSPA12A functions as an adaptor promoting nuclear translocation of PKM2, this discovery linked HSPA12A to macrophage M1 polarization and hepatocyte steatosis in NASH, providing the first defined intracellular binding partner and cellular mechanism.

    Evidence Co-IP, nuclear fractionation, and Hspa12a KO mice on high-fat diet

    PMID:30455376

    Open questions at the time
    • Direct binding interface between HSPA12A and PKM2 not mapped
    • Unclear whether HSPA12A chaperone ATPase activity is required for PKM2 translocation
  2. 2019 High

    Two studies broadened HSPA12A's partner repertoire: binding to SorLA's cytosolic domain in an ADP/ATP-dependent manner demonstrated canonical HSP70-like nucleotide-regulated interaction, while a PPARγ-HSPA12A positive feedback loop established HSPA12A's role in adipocyte differentiation.

    Evidence Pulldown and trafficking assays for SorLA binding; ChIP for PPARγ binding to Hspa12a promoter plus KO mouse adipogenesis studies

    PMID:30679749 PMID:30742088

    Open questions at the time
    • Whether the ATPase cycle of HSPA12A is catalytically active or structurally vestigial remains unresolved
    • How HSPA12A promotes PPARγ expression at the molecular level is not defined
  3. 2020 High

    HSPA12A was shown to promote PGC-1α nuclear translocation in hepatocytes to suppress pyroptosis, and separately to interact with HRD1 to drive CD147 ubiquitination and degradation in RCC cells, establishing HSPA12A as a general scaffolding protein that bridges partners for both transcriptional activation and proteasomal degradation.

    Evidence Co-IP plus KO mice for PGC-1α–AOAH–Caspase-11 axis; MS-identified HSPA12A–HRD1 interaction with CD147 stability assays in RCC cells

    PMID:32332915 PMID:32754264

    Open questions at the time
    • Whether HSPA12A simultaneously engages PGC-1α and HRD1 or these are cell-type-specific interactions is unknown
    • Structural basis of HSPA12A scaffolding is absent
  4. 2021 Medium

    HSPA12A was placed upstream of ERK/Akt signaling in endothelial barrier protection and confirmed to promote PGC-1α nuclear localization in skeletal muscle, extending its nuclear-translocation adaptor function to additional tissues.

    Evidence KO mice in acute lung injury plus ERK/Akt inhibitor epistasis in HUVECs; HSPA12A OE in myoblasts with PGC-1α inhibitor epistasis

    PMID:34343936 PMID:34793778

    Open questions at the time
    • How HSPA12A activates ERK/Akt phosphorylation—direct kinase interaction or indirect—is not resolved
    • PGC-1α results rely on pharmacological epistasis without direct binding domain mapping
  5. 2022 High

    HSPA12A was linked to angiogenesis via p38/ERK–AP-1 signaling in endothelial cells, while upstream regulation of HSPA12A itself was revealed: SRSF11-dependent alternative splicing of exon 2 controls HSPA12A transcript stability and N-cadherin-driven colorectal cancer metastasis.

    Evidence KO mice post-MI with p38/ERK inhibitor epistasis for angiogenesis; UV-CLIP and minigene assays for SRSF11–HSPA12A splicing regulation

    PMID:35783189 PMID:36394206

    Open questions at the time
    • Whether the exon 2-containing isoform has altered protein function versus only RNA stability effects is unclear
    • Direct HSPA12A–AP-1 interaction not demonstrated
  6. 2023 High

    A unifying metabolic theme emerged: HSPA12A suppresses hepatocyte glycolysis to reduce HMGB1 lactylation and exosomal secretion protecting against liver I/R injury, while in hippocampal neurons it sustains glycolysis via GSK3β inhibition for lactate-dependent neurogenesis—revealing tissue-specific directionality of HSPA12A's glycolytic regulation.

    Evidence Hepatocyte-specific HSPA12A OE/KO with HMGB1 lactylation and exosome assays; Hspa12a KO mice with CSF lactate measurement, BrdU labeling, and lactate rescue

    PMID:37441587 PMID:37580315

    Open questions at the time
    • Mechanism by which HSPA12A inhibits GSK3β is not defined at the molecular level
    • How HSPA12A achieves opposite glycolytic effects in hepatocytes versus neurons is unexplained
  7. 2024 High

    Multiple 2024 studies solidified HSPA12A's scaffolding mechanism: it bridges p53 and USP10 to stabilize p53 and suppress cardiac fibrosis; it promotes Smurf1-dependent HIF-1α stabilization to maintain glycolysis in cardiomyocytes and renal tubular cells; and it drives c-Myc nuclear translocation and lactylation for renal recovery, while in septic cardiomyopathy it activates mTOR to inhibit autophagy.

    Evidence Co-IP for ternary HSPA12A–p53–USP10 complex with KO mice post-MI; HIF-1α stability assays with Smurf1 dependence in cardiomyocytes and HK-2 cells; Co-IP for HSPA12A–c-Myc with nuclear fractionation in TECs; KO mice in CLP sepsis model with rapamycin epistasis

    PMID:38219869 PMID:38421727 PMID:39277835 PMID:39349238 PMID:39642573

    Open questions at the time
    • Whether HSPA12A directly binds Smurf1 or acts indirectly on HIF-1α stability is not established
    • Structural basis for simultaneous scaffolding of p53 and USP10 is unknown
    • How HSPA12A activates mTOR in cardiomyocytes is mechanistically undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: whether HSPA12A possesses functional ATPase activity, the structural basis of its multi-partner scaffolding, and the molecular determinants that produce opposing glycolytic effects across cell types.
  • No crystal or cryo-EM structure of HSPA12A exists
  • ATPase activity has not been directly measured
  • Cell-type-specific partner selectivity mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0044183 protein folding chaperone 4
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 3
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 1
Partners
HRD1MYCPGC1APKM2SMURF1SORLATP53USP10

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 HSPA12A selectively binds to the cytosolic domain of SorLA (an amyloid precursor protein receptor) in an ADP/ATP-dependent manner via specific acidic residues in SorLA's cytosolic domain, acting as an adaptor protein that affects both endocytic speed and subcellular localization of SorLA. Co-immunoprecipitation, pulldown, ADP/ATP-dependent binding assays, trafficking assays in cells Scientific reports Medium 30679749
2018 In macrophages, HSPA12A directly interacts with PKM2 (M2 isoform of pyruvate kinase) and promotes its nuclear translocation, thereby driving M1 macrophage polarization and secretion of proinflammatory cytokines, which paracrinally induces hepatocyte steatosis in NASH. Co-immunoprecipitation, loss- and gain-of-function studies, nuclear fractionation, high-fat diet mouse model with Hspa12a knockout Diabetes High 30455376
2020 HSPA12A directly interacts with PGC-1α and promotes its nuclear translocation in hepatocytes, thereby inducing AOAH expression which inactivates cytosolic LPS and suppresses Caspase-11-mediated hepatocyte pyroptosis (GSDMD cleavage). Co-immunoprecipitation, loss- and gain-of-function in primary hepatocytes, Hspa12a-/- mice, nuclear fractionation, AOAH overexpression rescue experiments Cell death and differentiation High 32332915
2019 HSPA12A is required for adipocyte differentiation through a positive feedback loop with PPARγ: PPARγ directly binds the PPAR response element in the Hspa12a promoter to drive HSPA12A expression, while HSPA12A in turn promotes PPARγ expression and adipogenic gene transcription during differentiation. Chromatin immunoprecipitation (ChIP) for PPARγ binding to Hspa12a promoter, Hspa12a-/- mice on HFD, PPARγ inhibitor (GW9662) rescue, gain/loss-of-function in primary adipocytes Cell death and differentiation High 30742088
2020 HSPA12A interacts with HRD1 ubiquitin E3 ligase in renal cell carcinoma (RCC) cells, promoting CD147 ubiquitination and proteasomal degradation, thereby reducing lactate export and glycolysis to suppress RCC cell migration. Mass spectrometry, co-immunoprecipitation, immunoblotting, cycloheximide/MG132 protein stability assays, CD147 overexpression rescue, wound healing and Transwell migration assays Theranostics High 32754264
2021 HSPA12A overexpression in endothelial cells increases phosphorylation of ERKs and Akt, maintaining VE-cadherin expression and reducing VEGF expression, thereby preserving endothelial barrier integrity and protecting against LPS-induced acute lung injury; pharmacological inhibition of either ERKs or Akt abolishes these protective effects. HSPA12A KO mice (in vivo ALI model), HSPA12A overexpression in HUVECs, phosphorylation assays, ERK/Akt inhibitors as epistasis, permeability assays International immunopharmacology Medium 34343936
2022 HSPA12A promotes angiogenesis in endothelial cells by activating p38 and ERK phosphorylation, which drives AP-1 phosphorylation and nuclear localization, increasing expression of VEGF, VEGFR2, and Ang-1; inhibition of p38 or ERK abolished HSPA12A-promoted angiogenesis. HSPA12A KO mice post-MI, HSPA12A overexpression in endothelial cells, phosphorylation assays, pharmacological inhibition of p38/ERK, tube formation/migration/proliferation assays Oxidative medicine and cellular longevity Medium 35783189
2022 SRSF11 regulates alternative splicing of HSPA12A pre-mRNA by directly binding a motif in exon 2 (shown by UV-CLIP and minigene assay); the HSPA12A transcript with exon 2 retention promotes RNA stability and increases N-cadherin expression, facilitating colorectal cancer metastasis. PAK5 phosphorylates SRSF11 at serine 287 to protect it from ubiquitination degradation, placing HSPA12A downstream in a PAK5/SRSF11/HSPA12A axis. UV crosslinking and immunoprecipitation (CLIP), minigene reporter assay, Co-IP, Phospho-tag SDS-PAGE, in vitro kinase assay, RNA-seq Clinical and translational medicine High 36394206
2023 HSPA12A overexpression suppresses glycolysis-generated lactate in hepatocytes, thereby reducing HMGB1 lactylation and its secretion in exosomes, which inhibits macrophage chemotaxis and inflammatory activation to protect against liver ischemia/reperfusion injury; HSPA12A knockout had opposite effects reversed by HMGB1 knockdown. Hepatocyte-specific HSPA12A overexpression, Hspa12a KO mice, Transwell chemotaxis assays, immunoprecipitation for lactylation, exosome HMGB1 measurement, HMGB1 knockdown rescue Theranostics High 37441587
2023 HSPA12A maintains cerebral lactate homeostasis by inhibiting GSK3β in hippocampal neurons to sustain glycolytic enzyme expression and lactate production; Hspa12a-/- mice showed mood instability and impaired adult hippocampal neurogenesis that were rescued by lactate administration. Hspa12a-/- mouse behavioral tests, CSF lactate measurement, BrdU labeling for neurogenesis, HSPA12A OE in primary hippocampal neurons, lactate rescue experiments Translational psychiatry Medium 37580315
2024 HSPA12A acts as a scaffolding protein binding both p53 and USP10 (ubiquitin specific protease 10) in cardiac fibroblasts, promoting USP10-mediated deubiquitination and stabilization of p53 protein, which then suppresses glycolysis and inhibits cardiac fibroblast activation and cardiac fibrosis. Co-immunoprecipitation-immunoblotting for HSPA12A-p53-USP10 ternary complex, cycloheximide/MG132 protein stability assays, Hspa12a KO mice post-MI, CF activation assays, Masson's trichrome staining Journal of advanced research High 38219869
2024 HSPA12A maintains aerobic glycolysis in cardiomyocytes during reperfusion by increasing Smurf1-mediated Hif1α protein stability, thereby upregulating glycolytic gene expression and sustaining Histone H3 lactylation; HSPA12A KO exacerbated MI/R-induced cardiomyocyte death and cardiac dysfunction. Hspa12a KO mice, gain/loss-of-function in cardiomyocytes, H3 lactylation assays, Hif1α protein stability assays (cycloheximide), Smurf1-dependent Hif1α stabilization, echocardiography JCI insight High 38421727
2024 HSPA12A directly interacts with c-Myc in renal tubular epithelial cells, enhancing c-Myc nuclear localization and lactylation (via Hif1α-dependent glycolysis-derived lactate), which drives proliferation-related gene expression and TEC proliferation to support renal recovery from ischemia/reperfusion injury. Co-immunoprecipitation for HSPA12A-c-Myc interaction, nuclear fractionation, c-Myc lactylation assays, Hif1α-dependent glycolysis experiments, Hspa12a KO mice post-KI/R, gain/loss-of-function in TEC Cellular and molecular life sciences High 39277835
2024 HSPA12A promotes Smurf1-dependent Hif1α protein stability (not transcription) to increase aerobic glycolytic flux and drive TEC proliferation after hypoxia/reoxygenation; glycolysis inhibition or Hif1α pharmacological inhibition (YC-1) abolished HSPA12A-promoted proliferation. Loss/gain-of-function in HK-2 cells, Hif1α protein stability assays, qPCR for transcription vs. protein, glycolysis inhibitors (2-DG, oxamate), pharmacological Hif1α inhibitor (YC-1) as epistasis Cell stress & chaperones Medium 39349238
2024 HSPA12A overexpression in cardiomyocytes activates mTOR and inhibits autophagy to enhance TLR4/MyD88/NF-κB-mediated inflammation; HSPA12A knockout protected against septic cardiomyopathy, and mTOR inhibition by rapamycin reversed HSPA12A-induced autophagy inhibition and inflammation. Hspa12a-/- mice (CLP sepsis model), HSPA12A OE in cardiomyocytes, mTOR/autophagy markers (LC3-II, p62), rapamycin epistasis, echocardiography, TUNEL/PI staining International immunopharmacology Medium 39642573
2021 HSPA12A protects skeletal muscle from bupivacaine-induced myotoxicity by promoting PGC1α expression and nuclear localization, thereby maintaining mitochondrial contents and integrity; PGC1α inhibition (SR-18292) abolished HSPA12A-mediated protection. HSPA12A OE in C2c12 myoblasts, bupivacaine myotoxicity model in mice and in vitro, mitochondrial content/fragmentation assays, PGC1α nuclear fractionation, PGC1α inhibitor (SR-18292) epistasis Toxicology and applied pharmacology Medium 34793778

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma. International journal of medical sciences 147 25798051
2023 Hepatocyte HSPA12A inhibits macrophage chemotaxis and activation to attenuate liver ischemia/reperfusion injury via suppressing glycolysis-mediated HMGB1 lactylation and secretion of hepatocytes. Theranostics 117 37441587
2020 HSPA12A attenuates lipopolysaccharide-induced liver injury through inhibiting caspase-11-mediated hepatocyte pyroptosis via PGC-1α-dependent acyloxyacyl hydrolase expression. Cell death and differentiation 83 32332915
2018 HSPA12A Is a Novel Player in Nonalcoholic Steatohepatitis via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization. Diabetes 66 30455376
2024 HSPA12A maintains aerobic glycolytic homeostasis and Histone3 lactylation in cardiomyocytes to attenuate myocardial ischemia/reperfusion injury. JCI insight 43 38421727
2019 HSPA12A is required for adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ. Cell death and differentiation 37 30742088
2020 HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma. Theranostics 29 32754264
2013 The response profiles of HSPA12A and TCTP from Mytilus galloprovincialis to pathogen and cadmium challenge. Fish & shellfish immunology 24 23643947
2022 Alternative splicing of HSPA12A pre-RNA by SRSF11 contributes to metastasis potential of colorectal cancer. Clinical and translational medicine 19 36394206
2024 HSPA12A acts as a scaffolding protein to inhibit cardiac fibroblast activation and cardiac fibrosis. Journal of advanced research 18 38219869
2024 HSPA12A promotes c-Myc lactylation-mediated proliferation of tubular epithelial cells to facilitate renal functional recovery from kidney ischemia/reperfusion injury. Cellular and molecular life sciences : CMLS 16 39277835
2015 Polymorphisms of PRLHR and HSPA12A and risk of gastric and colorectal cancer in the Chinese Han population. BMC gastroenterology 15 26302849
2023 HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization. Translational psychiatry 12 37580315
2021 HSPA12A improves endothelial integrity to attenuate lung injury during endotoxemia through activating ERKs and Akt-dependent signaling. International immunopharmacology 12 34343936
2019 HSPA12A targets the cytoplasmic domain and affects the trafficking of the Amyloid Precursor Protein receptor SorLA. Scientific reports 11 30679749
2022 HSPA12A Stimulates p38/ERK-AP-1 Signaling to Promote Angiogenesis and Is Required for Functional Recovery Postmyocardial Infarction. Oxidative medicine and cellular longevity 10 35783189
2024 Downregulation of HSPA12A protects heart against sepsis through suppressing mTOR-mediated inflammatory response in cardiomyocytes. International immunopharmacology 7 39642573
2024 HSPA12A stimulates "Smurf1-Hif1α-aerobic glycolysis" axis to promote proliferation of renal tubular epithelial cells after hypoxia/reoxygenation injury. Cell stress & chaperones 2 39349238
2023 HSPA12A was identified as a key driver in colorectal cancer GWAS loci 10q26.12 and modulated by an enhancer-promoter interaction. Archives of toxicology 2 37245169
2021 Downregulation of HSPA12A underlies myotoxicity of local anesthetic agent bupivacaine through inhibiting PGC1α-mediated mitochondrial integrity. Toxicology and applied pharmacology 0 34793778