Affinage

HSPA1L

Heat shock 70 kDa protein 1-like · UniProt P34931

Length
641 aa
Mass
70.4 kDa
Annotated
2026-04-28
38 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSPA1L is a constitutively expressed, MHC class III-linked member of the HSP70 chaperone family that functions as a cytoplasmic and stress-responsive nuclear chaperone with roles in protein quality control, mitophagy regulation, and receptor signaling. It binds peptides via its C-terminal substrate-binding domain, is phosphorylated by MK2 at Ser241 to enhance chaperone activity under heat stress, and undergoes crotonylation at K130 by VEGFR3 to promote PARKIN mitochondrial translocation and PARKIN-dependent mitophagy (PMID:11599570, PMID:31642047, PMID:39875989). HSPA1L modulates protein stability by competitively inhibiting GP78-mediated ubiquitination of PrPC, forms a complex with PrPC and COX4I at mitochondria to sustain mitochondrial membrane potential, and interacts with IGF1Rβ/integrin αV to activate AKT signaling while also directly binding the β-catenin promoter as a transcriptional activator (PMID:28759037, PMID:31965731, PMID:32971893). Despite high testicular expression, HSPA1L is dispensable for spermatogenesis and testicular heat-stress responses in knockout mice (PMID:32231871).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    Establishing that HSPA1L is a constitutively expressed, peptide-binding HSP70 family member with regulated subcellular localization answered the basic question of whether this MHC-linked chaperone is functionally active and inducible.

    Evidence Peptide-binding assays, immunofluorescence, and expression profiling across human cell lines and tissues

    PMID:11599570

    Open questions at the time
    • Endogenous client proteins not identified
    • Mechanism of nuclear translocation under heat shock not defined
    • No comparison of chaperone efficiency relative to HSPA1A/HSPA1B
  2. 2004 Medium

    Genetic mapping linked the HSPA1L M493T polymorphism in the peptide-binding domain, in combination with HLA-B*5701, to abacavir hypersensitivity, providing the first evidence that HSPA1L peptide-binding variation has immunological consequences.

    Evidence Fine genetic mapping, haplotype analysis, and ex vivo abacavir-stimulated TNF assay with CD8+ T cell depletion in patient cohorts

    PMID:15024131

    Open questions at the time
    • No biochemical reconstitution showing how M493T alters peptide presentation
    • Contribution of HSPA1L versus HLA-B*5701 not individually resolved
    • No structural basis for altered peptide binding
  3. 2017 High

    Demonstrating that HSPA1L binds GP78 and blocks GP78-mediated ubiquitination of PrPC established HSPA1L as a regulator of the ubiquitin-proteasome pathway, linking chaperone activity to protein turnover and tumor progression under hypoxia.

    Evidence Reciprocal co-immunoprecipitation, siRNA knockdown, ubiquitination assays, and in vivo xenograft in colorectal cancer cells

    PMID:28759037

    Open questions at the time
    • Structural basis of HSPA1L-GP78 interaction unknown
    • Whether HSPA1L regulates GP78 activity toward other substrates not tested
    • Hypoxia-dependent regulation of HSPA1L expression mechanism not defined
  4. 2017 High

    Identification of rare missense HSPA1L variants with decreased or dominant-negative chaperone activity in IBD patients established that HSPA1L functional variation has disease relevance and that its chaperone activity can be quantitatively assessed in vitro.

    Evidence Whole exome sequencing of IBD patients with in vitro biochemical chaperone activity assays of purified variant proteins

    PMID:28126021

    Open questions at the time
    • Causal relationship between HSPA1L variants and IBD pathogenesis not established
    • Dominant-negative mechanism not structurally explained
    • Decidualization link not mechanistically characterized
  5. 2019 High

    Identification of MK2-dependent phosphorylation at Ser241 that enhances chaperone activity defined a stress-activated post-translational regulatory mechanism for HSPA1L, explaining how its activity is tuned during cellular stress.

    Evidence Proteomics substrate screen, in vitro kinase assay, Ser241 mutagenesis, chaperone activity assay, and germ cell apoptosis assays

    PMID:31642047

    Open questions at the time
    • Whether Ser241 phosphorylation affects client specificity unknown
    • In vivo relevance of this phosphosite not confirmed in animal models
    • Dephosphorylation mechanism not identified
  6. 2020 High

    Showing that HSPA1L recruits PrPC to mitochondria and forms a ternary complex with COX4I to enhance mitochondrial function and regulate mitophagy established HSPA1L as a mitochondrial homeostasis factor in mesenchymal stem cells.

    Evidence Co-immunoprecipitation, mitochondrial fractionation, membrane potential and ROS assays, siRNA knockdown, and murine hindlimb ischemia model

    PMID:31965731

    Open questions at the time
    • How HSPA1L is directed to mitochondria not defined
    • Whether the HSPA1L-PrPC-COX4I complex forms in cell types other than MSCs unknown
    • Melatonin-dependent induction mechanism upstream of HSPA1L not characterized
  7. 2020 Medium

    HSPA1L was shown to interact with IGF1Rβ and integrin αV, activating AKT/NF-κB and AKT/GSK3β/β-catenin signaling, and to directly bind the β-catenin promoter, revealing a dual cytoplasmic–nuclear role in cancer stemness.

    Evidence Co-immunoprecipitation, ChIP, reporter assays, knockdown/overexpression in NSCLC cells

    PMID:32971893

    Open questions at the time
    • Transcription factor activity not confirmed by DNA-binding domain mapping
    • Whether nuclear HSPA1L transcriptional activity is chaperone-dependent unknown
    • Single-lab finding awaits independent validation
  8. 2020 High

    CRISPR knockout demonstrated that HSPA1L is dispensable for spermatogenesis and testicular heat-stress protection, resolving a long-standing assumption based on its high testicular expression.

    Evidence Hspa1l−/− mice generated by CRISPR/Cas9 with histology, TUNEL, sperm analysis, fertility testing, and heat-stress challenge

    PMID:32231871

    Open questions at the time
    • Compensatory upregulation of other HSP70 family members not fully assessed
    • Phenotypes under non-heat stresses (e.g., oxidative, proteotoxic) not tested
    • Tissue-specific conditional KO not performed
  9. 2021 Medium

    Identification of a vaspin–HSPA1L–GRP78–clathrin complex in proximal tubular cells linked HSPA1L to clathrin-mediated endocytosis and organelle stress protection in diabetic kidney disease.

    Evidence Co-immunoprecipitation, HSPA1L overexpression, vaspin-knockout mouse model, ER/lysosome/autophagy stress markers

    PMID:33742129

    Open questions at the time
    • Direct binding between HSPA1L and clathrin not confirmed by binary assay
    • How HSPA1L alleviates ER stress mechanistically is not defined
    • Stoichiometry and stability of the vaspin–HSPA1L–GRP78 complex not characterized
  10. 2024 Medium

    MFG-E8 was shown to interact with HSPA1L and suppress Parkin expression through an HSPA1L-Parkin pathway, inhibiting mitophagy in diabetic sarcopenia, positioning HSPA1L as a node linking extracellular signals to mitophagy regulation.

    Evidence Co-immunoprecipitation, siRNA knockdown, western blotting, diabetic sarcopenia mouse model

    PMID:38553831

    Open questions at the time
    • Mechanism by which HSPA1L-MFG-E8 interaction downregulates Parkin is unknown
    • Whether HSPA1L directly binds Parkin or acts indirectly not resolved
    • Single-lab finding
  11. 2025 High

    VEGFR3-mediated crotonylation of HSPA1L at K130 was shown to be required for PARKIN mitochondrial translocation and mitophagy, establishing a novel post-translational modification that governs HSPA1L's mitophagy-regulatory function.

    Evidence LC-MS/MS identification of interaction and K130 crotonylation site, K130R mutagenesis, co-immunoprecipitation, Ang II-induced injury models in vitro and in vivo

    PMID:39875989

    Open questions at the time
    • Enzyme catalyzing K130 crotonylation not identified (VEGFR3 is a kinase, not a known crotonyltransferase)
    • Whether K130 crotonylation affects chaperone activity per se not tested
    • Structural basis for crotonylation-dependent PARKIN recruitment unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The relationship between HSPA1L's multiple post-translational modifications (Ser241 phosphorylation, K130 crotonylation), its client specificity across cellular contexts, and its apparently redundant role in spermatogenesis remains unintegrated into a unified regulatory model.
  • No structural model of HSPA1L with bound clients or in modified states
  • Systematic identification of endogenous substrates/clients not performed
  • Functional redundancy with HSPA1A/HSPA1B not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 3 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
COX4I1FLT4GP78HSPA5IGF1RITGAVMFGE8PRNP
Complex memberships
HSPA1L-IGF1Rβ-integrin αV complexHSPA1L-PrPC-COX4I mitochondrial complexvaspin-HSPA1L-GRP78-clathrin complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 HSPA1L (Hsp70-Hom) was shown to have peptide-binding specificity, is endogenously expressed in human cell lines, localizes to the cytoplasm under basal conditions and concentrates in the nucleus after heat shock, and is specifically upregulated by interferon-gamma and LPS treatment. Peptide binding assays, immunofluorescence, subcellular fractionation, western blotting, RT-PCR across tissues and cell lines Cell stress & chaperones High 11599570
2019 MAPKAP kinase 2 (MK2) phosphorylates HspA1L specifically on Ser241 within the N-terminal nucleotide-binding domain, and this phosphorylation enhances HspA1L chaperone activity in vitro and protects male germ cells from heat stress-induced apoptosis. Proteomics-based substrate screen, in vitro kinase assay, site-directed mutagenesis, chaperone activity assay, cell viability/apoptosis assays in germ cells Cell stress & chaperones High 31642047
2017 In hypoxic colorectal cancer cells, HSPA1L interacts with the E3 ubiquitin ligase GP78 and inhibits GP78-mediated ubiquitination and degradation of cellular prion protein (PrPC), thereby promoting PrPC accumulation and tumor progression; HSPA1L knockdown restored GP78-PrPC interaction and increased PrPC ubiquitination. Co-immunoprecipitation, knockdown (siRNA), ubiquitination assay, in vivo xenograft, western blotting Oncogene High 28759037
2017 De novo and rare missense mutations in HSPA1L identified in IBD patients result in decreased chaperone activity in vitro; three variants also showed dominant negative effects on both HSPA1L and HSPA1A chaperone activity. In vitro functional assay linked HSPA1L activity to decidualization. Whole exome sequencing, in vitro chaperone activity biochemical assay of variant proteins, dominant negative assay Genome medicine High 28126021
2020 Melatonin-induced HSPA1L binds to cellular prion protein (PrPC), recruits PrPC to mitochondria, and the HSPA1L-PrPC complex then binds to COX4I (mitochondrial complex IV protein), increasing mitochondrial membrane potential and antioxidant enzyme activity; HSPA1L knockdown blocked these protective effects and abrogated melatonin-mediated rescue of mitophagy in senescent MSCs. Co-immunoprecipitation, siRNA knockdown, mitochondrial fractionation, mitochondrial membrane potential assay, ROS/antioxidant assay, murine hindlimb ischemia model Aging cell High 31965731
2020 HSPA1L interacts directly with IGF1Rβ and integrin αV to form a triple complex that activates IGF1Rβ signaling through AKT/NF-κB and AKT/GSK3β/β-catenin pathways; additionally, HSPA1L is present in the nucleus and directly binds the β-catenin promoter to function as a transcriptional activator, regulating ALDH1 expression and cancer stem cell properties in NSCLC cells. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), knockdown/overexpression, reporter assays, flow cytometry for ALDH1 International journal of molecular sciences Medium 32971893
2021 During internalization into proximal tubular cells, vaspin forms a complex with HSPA1L and GRP78; both vaspin partners bind to clathrin heavy chain and are involved in endocytosis. Overexpression of HSPA1L alleviated organelle stresses (ER stress, autophagy impairment, lysosome dysfunction) in diabetic kidney disease. Co-immunoprecipitation, overexpression, vaspin-/- mouse model, organelle stress assays (ER, lysosome, autophagy markers) Communications biology Medium 33742129
2024 MFG-E8 interacts with HSPA1L (identified by Co-IP), and elevated MFG-E8 downregulates Parkin expression via the HSPA1L-Parkin pathway, inhibiting mitophagy in diabetic sarcopenia; disruption of this pathway by MFG-E8 siRNA rescued mitophagy. Immunoprecipitation, Co-immunoprecipitation, siRNA knockdown, western blotting, in vivo mouse model Journal of cachexia, sarcopenia and muscle Medium 38553831
2025 VEGFR3 binds directly to HSPA1L via its disorder domain (identified by LC-MS/MS and Co-IP), and crotonylation of HSPA1L at K130 by VEGFR3 is required for promoting PARKIN mitochondrial translocation and PARKIN-dependent mitophagy; K130R mutation abolished these protective effects in Ang II-induced proximal tubular cells. LC-MS/MS, Co-immunoprecipitation, site-directed mutagenesis (K130R), in vitro and in vivo (Ang II mouse model) functional assays Cell communication and signaling High 39875989
2004 A nonsynonymous polymorphism in HSPA1L (M493T, in the peptide-binding domain) in combination with HLA-B*5701 was identified as necessary for abacavir hypersensitivity; abacavir-stimulated monocyte TNF expression was abrogated by CD8+ T cell depletion, indicating an HLA-B*5701-restricted immune mechanism. Fine genetic mapping, haplotype analysis, ex vivo abacavir stimulation with CD8+ T cell depletion, cohort study Proceedings of the National Academy of Sciences of the United States of America Medium 15024131
2018 Rare, likely damaging missense variants in HSPA1L were identified in families with recurrent spontaneous preterm birth; in silico analysis predicted an additional phosphorylation site from rs34620296 that could affect chaperone activity or protein stability, and in vitro functional experiments showed a link between HSPA1L activity and decidualization. Whole exome sequencing, in silico phosphorylation prediction, in vitro decidualization functional assay PLoS genetics Low 30001343
2019 Overexpression of HSPA1L (either C or T allele of +2437 SNP) in neuroblastoma cells and rat MCAO model reduced neuronal apoptosis under hypoxia/ischemia by upregulating PI3K/p-AKT and downregulating BAX; the T allele showed stronger neuroprotection than the C allele. Lentiviral overexpression, neuronal hypoxic injury model (DFO), rat MCAO model, TTC staining, western blotting for apoptotic proteins Gene Medium 31170438
2020 Hspa1l knockout mice (CRISPR/Cas9) show no defect in spermatogenesis, sperm count, sperm motility, or fertility, and heat stress does not exacerbate testicular apoptosis in Hspa1l-/- mice, demonstrating that HSPA1L is dispensable for physiological spermatogenesis and heat stress responses in the testis. CRISPR/Cas9 knockout, histology, TUNEL assay, sperm motility and count analysis, fertility testing, heat stress challenge PeerJ High 32231871

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proceedings of the National Academy of Sciences of the United States of America 336 15024131
1993 Polymorphic analysis of the human MHC-linked heat shock protein 70 (HSP70-2) and HSP70-Hom genes in insulin-dependent diabetes mellitus (IDDM). Scandinavian journal of immunology 109 7901896
2020 Melatonin suppresses senescence-derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L-mitophagy pathway. Aging cell 74 31965731
2003 Heat shock protein 70 genotypes HSPA1B and HSPA1L influence cytokine concentrations and interfere with outcome after major injury. Critical care medicine 62 12544996
2005 HSP70-hom gene polymorphism in allogeneic hematopoietic stem-cell transplant recipients correlates with the development of acute graft-versus-host disease. Transplantation 40 15818324
2018 Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth. PLoS genetics 38 30001343
2021 SARS-CoV-2 Infection-Induced Promoter Hypomethylation as an Epigenetic Modulator of Heat Shock Protein A1L (HSPA1L) Gene. Frontiers in genetics 35 33679887
2017 Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis. Oncogene 35 28759037
2016 Modification of embryonic resistance to heat shock in cattle by melatonin and genetic variation in HSPA1L. Journal of dairy science 35 27614828
2001 Characterization and regulation of the major histocompatibility complex-encoded proteins Hsp70-Hom and Hsp70-1/2. Cell stress & chaperones 32 11599570
2006 HSP70-hom gene single nucleotide (+2763 G/A and +2437 C/T) polymorphisms in sarcoidosis. International journal of immunogenetics 31 16611259
2009 TNF, LTA, HSPA1L and HLA-DR gene polymorphisms in HIV-positive patients with hypersensitivity to cotrimoxazole. Pharmacogenomics 30 19374512
2005 Polymorphisms of heat shock protein 70 gene (HSPA1A, HSPA1B and HSPA1L) and schizophrenia. Neuroscience research 30 15963589
2017 De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease. Genome medicine 23 28126021
2000 A novel variant of the MHC-linked hsp70, hsp70-hom, is associated with rheumatoid arthritis. Tissue antigens 21 10958354
1994 HSP70-Hom NcoI polymorphism and HLA-associations in the Finnish population and in patients with ankylosing spondylitis or reactive arthritis. European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics 20 9098422
2020 The heat shock protein family gene Hspa1l in male mice is dispensable for fertility. PeerJ 18 32231871
2024 The regulation of MFG-E8 on the mitophagy in diabetic sarcopenia via the HSPA1L-Parkin pathway and the effect of D-pinitol. Journal of cachexia, sarcopenia and muscle 17 38553831
2021 A Vaspin-HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease. Communications biology 17 33742129
2020 HSPA1L Enhances Cancer Stem Cell-Like Properties by Activating IGF1Rβ and Regulating β-Catenin Transcription. International journal of molecular sciences 16 32971893
2017 Polymorphisms of heat shock protein 70 genes (HSPA1A, HSPA1B and HSPA1L) and susceptibility of noise-induced hearing loss in a Chinese population: A case-control study. PloS one 12 28182740
2012 Association of hsp70-2 (+1267A/G), hsp70-hom (+2437T/C), HMOX-1 (number of GT repeats) and TNF-alpha (+489G/A) polymorphisms with COPD in Croatian population. Clinical biochemistry 12 22542718
2019 MAPKAP kinase 2-mediated phosphorylation of HspA1L protects male germ cells from heat stress-induced apoptosis. Cell stress & chaperones 10 31642047
2010 Synergistic effect and VEGF/HSP70-hom haplotype analysis: relationship to prostate cancer risk and clinical outcome. Human immunology 10 20096741
2019 HSPA1L and HSPA1B gene polymorphisms and haplotypes are associated with idiopathic male infertility in Iranian population. European journal of obstetrics, gynecology, and reproductive biology 9 31228677
2007 Association of HSP70-hom genetic variant with prostate cancer risk. Molecular biology reports 9 17578680
2019 The differential neuroprotection of HSP70-hom gene single nucleotide polymorphisms: In vitro (neuronal hypoxic injury model) and in vivo (rat MCAO model) studies. Gene 6 31170438
2018 Association Studies of HSPA1A and HSPA1L Gene Polymorphisms With Schizophrenia. Archives of medical research 6 30342847
2015 Analysis of IL-6, STAT3 and HSPA1L gene polymorphisms in anti-tuberculosis drug-induced hepatitis in a nested case-control study. PloS one 6 25789467
2015 Genetic polymorphisms of hspa1b and hspa1l in infertile men. JPMA. The Journal of the Pakistan Medical Association 5 26160076
2006 Polymorphisms of heat shock protein-70 (HSPA1B and HSPA1L loci) do not influence infection or outcome risk in critically ill surgical patients. Shock (Augusta, Ga.) 5 16525348
2015 Elevated level of HSPA1L mRNA correlates with graft-versus-host disease. Transplant immunology 4 25680846
2014 HSP70-hom gene polymorphisms modify the association of diethylhexyl phthalates with insulin resistance. Environmental and molecular mutagenesis 4 25044062
2025 VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L. Cell communication and signaling : CCS 3 39875989
2010 Patient HSP70-hom TG haplotype is associated with decreased transplant-related mortality and improved survival after sibling HLA-matched hematopoietic stem cell transplantation. Clinical transplantation 3 19758266
2026 Evaluating the Effect of RNA Interference of Two Heat Shock Proteins (HSPA1L, HSP90B1) in Inducing Apoptosis in Acyrthosiphon Pisum. Biochemistry & molecular biology journal 0 42039770
2020 HSPA1L rs1061581 polymorphism is associated with the risk of preeclampsia in Han Chinese women. Bioscience reports 0 32039449
2016 [Interaction Between Occupational Vanadium Exposure and hsp70-hom on Neurobehavioral Function]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 0 27062781